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1. Introduction
Epigenetics is a branch of genetics that focuses on the heritable changes of DNA or associated proteins, other than DNA sequence variations, which carry information content during cell division [1,2]. These heritable changes are ascribed to chromatin, which constitutes the ultrastructure of DNA and whose modifications affect the genetic material functionality. Differences in chromatin structure have been associated to transcription regulation [3-5] and chromosome stability [6,7], affecting both gene’s information, expression and heritability. Noteworthy, these epigenetic modifications are involved in both transcriptional activation and repression, indicating their widespread role as modulators of gene expression in numerous biological processes [8,9].
Chromatin is subjected to numerous modifications roughly classified in two groups: DNA and histone post-translational modifications (histone-PTMs).
DNA methylation is the most studied epigenetic modification of DNA and corresponds to the covalent addition of a methyl (CH3) group to the nucleotide cytosine within CG dinucleotides or CNG trinucleotides where N can be C, A, G or T. Usually, DNA methylation induces decreased protein-DNA binding of transcription factors and leads to the repression of gene expression [10].
DNA “methylable” sequences are not uniform across the human genome but restricted in CpG rich DNA regions termed CpG islands (CGI). CGI are localized at repetitive sequences, heavy methylated, to prevent the reactivation of endoparasitic sequences such as transposons, and at gene promoter sequences, which are normally refractory to methylation in normal somatic cells [8,11].
DNA methylation is specifically established by DNA methyltransferases proteins (DNMTs), which can be recruited by numerous DNA-binding molecular complexes. These enzymes were classically classified in two categories: de novo DNMTs, as mammalian DNMT3a and DNMT3b, in charge of the addition of the methyl group on a previously unmethylated DNA, and maintenance DNMTs, whose only known member is DNMT1, responsible for methylation renewal in the newly synthesized DNA copy. However, this classification does not entirely explain methylation establishment and maintenance in various molecular processes [10]. For instance, a number of studies demonstrated that all DNMTs are important in the maintenance of methylation during DNA replication, therefore indicating that it is not possible to distinguish classes of DNMTs based on their functional role [12-15]. Another important functional role in DNA methylation dynamics is constituted by the removal of methyl group, which is required to activate methylated genes. However, demethylation is a process not fully understood, in fact, until recently, it was current opinion that only a passive demethylation could occur, as a consequence of a lack of methylation maintenance during DNA replication. The discovery of several putative demethylases, as thymine DNA glycosylase (TDG), methyl-binding domain 2 (MBD2), and GADD45 [16-18], strongly suggested that an active mechanism of demethylation can occur in specific contexts, such as germ line reprogramming [19-22].
The second group of epigenetic changes is represented by histone post-translational modifications (PTM), which consist in the addition of chemical groups to amino acid residues of both canonical histones (H2A, H2B, H3 and H4) and variant histones (such as H3.1, H3.3 and HTZ.1).
Differently from DNA modifications, there are at least eight distinct types of histone post-translational modifications: acetylation, methylation, phosphorylation, ubiquitylation, sumoylation, ADP ribosylation, deimination, and proline isomerization. Each chemical group can be established at multiple amino acid residues of nucleosomes in multiple levels of substrate modification by specific classes of enzymes. For example, lysine methylation can be established at numerous aminoacidic residues of N-terminus tails of histones H3 and H4, such as K4, K9, K20 and K27, in mono-, di- or tri-methylated forms. This variety of histone PTMs and its timing of appearance depends on the particular cell conditions giving the cells different functional responses [23]. Differently from DNA methylation, histone PTMs feature numerous functional roles. For instance, histone acetylation regulates DNA replication, repair and condensation; methylation, phosphorylation and ubiquitylation are involved in DNA repair or condensation. Moreover, all PTMs regulate transcription processes; acetylation is generally a marker of transcriptionally active genes, and methylation can be a marker of repressed or active genes depending on the amino-acid residues involved. For example, methylation of histone H3 lysine 4 (H3K4me) is considered a mark of transcriptionally active genes, while methylation of histone H3 lysine 9 and 27 (H3K9me; H3K27) are considered a mark of transcriptionally repressed genes [8,11,23].
Almost all cellular processes that require transcription dynamics and genetic stability can be considered epigenetic processes. Cellular differentiation is a good example of biological process, which is strictly connected to epigenetics. The genome sequence is static and it is the same for each cell of an organism (with some exceptions); however, cells are able to differentiate into many different types, with different morphology and physiological functions. During organism development, the zygote, derived form a single fertilized egg cell, originates totipotent cells, able to potentially differentiate in all cell types of adult organisms. After several divisions, totipotent cells originate pluripotent cells, which are partially differentiated and able to differentiate in several cell types. Finally, pluripotent cells complete differentiation becoming adult somatic cells. The differentiation processes are characterized by transcriptional activation and repression of specific genes and, once completed, the cells maintain their characteristic gene-expression pattern, strictly dependent on the epigenetic modifications previously established [24]. Therefore, cell differentiation is rigorously related to the establishment of the correct epigenetic status and to the proper epigenetic maintenance. Epigenetic abnormalities alter gene expression, counteracting regular differentiation and cell physiology [25]. In support of this theory, cancer cells feature an aberrant epigenetic landscape, indicating the causal relationship between epigenome dynamics and cellular processes as proliferation, cellular identity maintenance and genomic instability. [26-28]. Frequently, CGIs in the proximity of tumor suppressor genes (TSG) are methylated in various cancers, inducing TSGs transcriptional repression and promoting cancer progression [29]. Furthermore, specific patterns of histones H3 and H4 acetylation and methylation are associated with numerous cancer types, and it has been shown that several epigenetic patterns enable to distinguish disease subtypes [30,31].
This chapter explores the role of the Enhancer of Zeste Homolog 2 (EZH2). EZH2, the catalytic subunit of Polycomb repressive complex 2, catalyzes the addition of methyl groups to lysine 27 of the N-tail of histone H3 (H3K27me). The importance to specifically focus on EZH2 raises from the evidence that it is involved in several differentiation processes and is often over-expressed in a wide variety of cancer types [32].
2. PcG proteins and PRC-mediated silencing
Polycomb group proteins (PcG) were discovered in Drosophila melanogaster as responsible of homeotic gene silencing, also referred as Hox clusters. Hox proteins are a group of transcription factors that determine cell identity along the anteroposterior axis of the body plan by the transcriptional regulation of hundreds of genes [33-42]. After the initial discovery in fruit flies, PcG proteins were detected in plants and in mammals, where they are involved in development, stem cell biology and cancer [43-48]. Polycomb-mediated gene silencing is required in many processes like mammalian X-chromosome inactivation and imprinting [49,50]. Furthermore, PcG proteins are required to maintain stem cell identity [51]. Indeed, their numerous target genes encode for transcription factors and signaling components involved in cell fate decision, therefore in differentiation processes [32].
Principal PcG proteins are conserved from Drosophila to human indicating that PcG-mediated gene silencing is conserved among eukaryotes [42,52,53]. In mammals, each of the fly proteins has two or more homologs [54]. PcG proteins form two main complexes: Polycomb-repressive complex 1 and 2 (PRC1, PRC2) [55-59].
In mammals PRC1 is formed by BMI1, RING1A/B, CBX, and PHC subunits [60]. RING1A/B are ubiquitin E3 ligases that catalyze the monoubiquitylation of histone H2A at lysine 119 (H2AK119ub1), a histone PTM associated with transcriptional silencing [48,53].
As previously explained, PRC2 has a histone methyltransferase activity on lysine-27 of histone H3 [56-59]. EZH2 is the catalytic subunit of the complex and is activated by other PRC2 subunits like EED, SUZ1 and RbAp46 [61,62]. Recent studies have identified an EZH2 homolog, EZH1 that originates an alternative PRC2 complex and, as EZH2, is able to methylate H3K27. EZH1 and EZH2 can occupy similar target genes, and in some cases have been proposed to play redundant roles. However, during development, it has been demonstrated that the two proteins, can also have distinct and context-dependent roles [63-65].
PRC1 and PRC2 are able to induce gene silencing independently by each other [66,67] or by a synergistic mechanism. In fact, establishment of H3K27me3 by PRC2 complex can induce the recruitment of PRC1 by binding the chromodomain of the PHC subunits [39,58]. Once recruited, PRC1 induces transcriptional repression of target gene by catalyzing the ubiquitilation of lysine 119 of histone H2 or by an H2Aub-independent mechanism [68-70]. Therefore, in gene promoters of PRC1 and PRC2 common target genes, H3K27me3, can be reckoned as the hallmark of PcG mediated repression, whereas PRC1 carries out the gene silencing (Figure 1) [48,71].
Figure 1.
Epigenetic gene silencing PcG-mediated. PRC2 induces EZH2-mediated H3K27me3. H3K27me3 recruits PRC1 that ubiquitylates H2AK119 promoting chromatin compaction and gene silencing.
For what concerns PRC1-independent target genes, it has been shown that PRC2 is able to catalyze in vitro the methylation of lysine 26 of histone H1, which in turn recruits heterochromatin binding protein 1 (HP1) to chromatin, influencing its structure [72,73].
PRC2 is also able to cooperate with other epigenetic silencing enzymes. Recent studies demonstrated that it acts upstream of DNMTs in order to silence target genes [74]. The mechanism is not yet clear, but a hypothesis is that target genes are initially repressed through histone H3K27 methylation. Afterwards, PRC2 induces a more stable transcriptional silencing by recruiting DNMTs and establishing CGI methylation [75-77]. Moreover, PRC2 associates with histone deacetylases, reinforcing transcriptional repression and providing functional synergy to stable silencing of target genes (Figure 2) [32,56-59,61,78,79].
The functional link between PcG proteins, HDACs and DMTs demonstrated a synergic control of gene silencing involved in both physiological and pathological processes.
Figure 2.
Functional link between PRC2 HDACs and DNMTs. Target genes are initially deacetylated by a histone deacetylase. PRC2 silences target genes by H3K27me3. PRC2 may also recruit DNMTs that methylate DNA promoting a more strongly silenced chromatin state.
3. Regulation of PRC2 activity
Polycomb group proteins are epigenetic regulators of embryonic development and stem cell maintenance [48,51,80] and their deregulation contributes to cancer [28,81]. The crucial role of Polycomb-repressive complexes in the regulation of these biological processes strongly supports the presence of multiple molecular mechanisms involved in PRC activity modulation, such as regulation of expression, post-translational modification and recruitment of other molecular complexes to target genes.
3.1. Regulation of PRC2 components expression
As already explained, PRC2 functions are strictly tissue-specific. Therefore, it should not surprise that the expression of PRC2 subunits has been reported to be context- and tissue-specific, despite the activity of PRC2 promoters has not yet fully understood. Recently, it has been proposed a general rule by which PRC2 expression is maintained by molecular factors that control cell proliferation and self-renewal, such as E2F factors and c-myc, whereas its transcriptional repression is induced by differentiation-promoting factors, such as pRb and p16INK4b [65,82-85].
For what concerns the transcriptional regulation by the pRb/E2F pathway, it has been demonstrated that E2F factors are required for the transcriptional activity of EZH2 and EED in mouse embryonic fibroblasts (MEF). Ectopic expression of pRb and p16INK4b, both involved in E2F target gene repression, induces PRC2 subunits transcriptional repression, whereas pRb silencing increases their transcript levels [82-84].
Furthermore, it has been recently reported that c-myc, a key regulator of ES cells pluripotency maintenance, is directly involved in transcriptional upregulation of all components of PRC2; c-myc binds PRC2 subunits promoters and induces the acetylation of histones H3 and H4, an epigenetic modification involved in transcriptional activation [85].
Finally, it has been demonstrated that EZH2 is post-transcriptionally regulated by a microRNAs-mediated translation-inhibition mechanism. MicroRNAs (miRNAs) are small non-coding RNA ~22 nt long (ncRNA), involved in various biological processes, which exert gene expression regulation. Several studies showed a role of miRNA in chromatin structure, they are indeed able to regulate transcriptional levels of epigenetic enzymes as for example PcG proteins [86,87]. Initially, it has been shown that miRNA-101 and miRNA-26a negatively regulate EZH2 expression by binding to its 3’-UTR. However, recent studies have reported an increasing number of miRNAs, able to inhibit the translation of PRC2 subunits (reviewed in [87]). For example, miR-214 regulates EZH2 expression during muscle differentiation [88]. Furthermore, downregulation of several miRNAs promotes EZH2 overexpression in cancer; for instance, miR-25 and miR30d in thyroid carcinoma [89], let-7 in prostate cancer [90], miR-98 and miR-214 in esophageal squamous cell carcinoma.
3.2. Post-translational modification of EZH2
Several studies demonstrated that post-translational modifications of PRC2 subunits can regulate their recruitment to target genes and molecular activity [91-93].
The first post-translational modification that will be analyzed is EZH2 phosphorylation, which has been extensively studied. In order to bind to PRC2 complex and exert its molecular function, EZH2 must be phosphorylated in several specific sites. EZH2 phosphorylation can be classified in two groups: dependent by cell-cycle-dependent signals and dependent by extracellular-regulated kinases [94]. In the first mechanism, EZH2 is phosphorylated by Cdk1 and Cdk2 during cell cycle progression [92,93,95]. In murine model, phosphorylation of threonine 345 (Thr345) increases the binding of EZH2 to specific regulatory ncRNAs as HOTAIR that induces the recruitment of PRC2 to HOX gene promoters, and Xist RepA that induces the inactivation of X chromosome [93]. In humans, phosphorylation of threonine 350 (Thr350) corresponds to murine Thr345. Recently, Chen and collaborators demonstrated a crucial role for the phosphorylation of Thr350 by Cdk1 and Cdk2 in both EZH2-dependent gene silencing and EZH2-mediated cell proliferation and migration [92].
Moreover, Cdk1 is able to phosphorylate EZH2 at Thr487. This modification is associated with the disruption of EZH2 binding with other PRC2 components with subsequent methyltransferase activity inhibition [95]. Surprisingly, these data are in contrast with studies of Kaneco and coworkers, which demonstrated that EZH2 phosphorylated at Thr487 is able to bind other subunits of PRC2 complex and to maintain its activity. In addition, another recent work showed that inhibition of Cdk1 suppresses hoxA gene expression in contrast to the findings of Chen and colleagues. [92,93,95]. Bearing in mind that these three findings use different models to analyze EZH2 phosphorylation, becomes noticeable that the apparent discrepancies could be explained with different mechanisms of tissue-specific regulation. Further studies are needed to resolve these specific incongruities. Mechanisms of EZH2 regulation during cell cycle are summarized in figure 3.
Figure 3.
Model for regulation of EZH2 activity during cell cycle. PRC2 subunits are E2Fs target genes. E2Fs activity is inhibited by hypo-phosphorylated pRb during G1 phase of cell cycle. Activity of Cdk/cyclin complexes triggers the transition from G1 to S phase through phoshorylation of pRb and consequent activation of E2F target genes. Moreover Cdk2 and Cdk1 are able to phosphorylate EZH2 promoting the binding of ncRNA, a crucial step for the recruitment of PRC2 to its target genes.
Phosphorylation of EZH2 is also modulated by environmental signals. Extracellular signals induce Akt activation that in turn is able to phosphorylate EZH2 at Serine 21 (Ser21), which results in a suppression of the PRC2 activity. Differently by previous phosphorylation mechanisms, Akt-dependent phosphorylation does not affect the binding with other PRC2 components but it reduces the affinity of EZH2 with histone H3, which results in a decrease of the H3K27 methylation and consequent de-repression of the EZH2-silenced genes [96].
Furthermore, recent studies reported that EZH2 can be phosphorylated at threonine 372 (Thr372) by p38α kinase in muscle stem (satellite) cells in response to tumor necrosis factor (TNF), an inflammatory cytokine highly expressed in muscle regeneration process [97]. The phosphorylation of EZH2 at Thr372 promotes the repression of Pax7, a marker of stem cells, by inducing the interaction between PRC2, YY1 and PRC1. This leads to the transcriptional activation of genes involved in muscle regeneration and to transcriptional repression of genes involved in cell proliferation. This data are in apparent conflict with the fully studied role of EZH2 in the cell proliferation promotion, but it is possible that in response to specific signals and in particular cell types, PRC2 can silence genes involved in cell cycle regulation, resulting in an antiproliferative activity [97]. Other studies are needed to confirm this hypothesis.
Finally EZH2 and SUZ12 can be sumoylated in vitro and in vivo but the role of this modification is still not yet clear [91].
3.3. PRC2 recruitment to target genes
PRC2 core subunits bind to the DNA sequences with low affinity, this, therefore, suggests the existence of recruiting mechanisms that direct PRC2 to target genes [98].
In Drosophila melanogaster, PcGs are recruited by Polycomb response elements (PREs), DNA sequences of several hundred base pairs [42,48,99] located both in proximal region of gene promoters and in long-range enhancer elements. PREs contain consensus sequences for various transcription factors [100]. For instance, Drosophila’s pleiohomeotic (PHO) and pleiohomeotic-like (PHO-like) are PcG proteins conserved in mammalian cells and involved in the recruitment of PRC complexes.
It is important to stress that PREs are element and not short stretches of nucleotides and contain numerous TF binding sites, therefore, although several Drosophila transcription factors are essential for the recruitment of PRC complexes to specific promoters, a single TF is not sufficient alone. Moreover, “universal” factors able to bind all PcG target genes have not been found yet, and it is strongly suggested that the PcG protein recruitment is a cell type-specific mechanism dependent by various combinations of TFs [52,53]. Mammalian PREs have been just recently discovered [101]. The mammalian orthologue of Drosophila DNA-binding protein PHO is YY1, however, studies in mouse stem cells showed a little overlap between sequences bound by YY1 and PRC2 suggesting a cell-type specific role rather than a general one [47].
Similar to YY1, the embryonic stem (ES) cell-related transcription factors OCT4, SOX2 and NANOG co-occupy a subset of PcG target genes in human and mouse ES cells [45,46]. Interestingly, recent studies demonstrated that the serine/threonine protein phosphatase-1 (PP1), together with its regulatory partner NPP1, is capable of complexing PRC2 at its target genes, modulating the DNA occupancy of EZH2 and therefore its activity [102].
Current data suggest that, similarly to flies, various transcription factors may be involved in the recruitment of mammalian PRC2, varying in different cell types and context. Recent studies showed that Twist-1 recruits EZH2 at ARF-INK4a locus in Mesenchymal Stem Cells (MSCs), inducing transcriptional repression of both p14ARF and p16INK4a, and suppression of senescence initiation [103].
Moreover, PRC2 can also be associated with another PcG protein, called PHF1. PHF1 is not a core subunit of PRC2 but its association with the complex influences the recruitment of PRC2 to target genes and stimulates the enzymatic activity [104,105].
Furthermore, several reports have identified in mouse and human ES cells, a novel DNA-binding component of PRC2 complex, Jarid2, which is a member of the Jumonji C (JmjC) family that binds GC and GA-rich motifs [106-109]. Despite this, it has been demonstrated that Jarid2 promotes PRC2 recruitment to target genes, but its precise role in PRC2 activity has not yet been defined. Knockdown of Jarid2 causes an increase of H3K27me3 levels on some PRC2-target genes [106,107] and a decrease on others [108,109]. Different effects of Jarid2 on PRC2 activity could depend from additional factors, and it has been suggested that it acts as a ‘‘molecular rheostat’’ that finely calibrates PRC2 functions at developmental genes [106].
Finally, long ncRNAs have been implicated in the recruitment of PRC2 [48,53,80,81,110]. For example, in primary human fibroblasts the ncRNA HOTAIR recruits PRC2 complex to HOXD locus for regulating gene silencing in trans [111]. Several long ncRNA have been discovered and its tissue-specific expression allows assuming PRC2-dependent roles in organogenesis [112].
4. Role of PRC2 in differentiation and cell fate commitment
In past decades, several studies demonstrated that PcG proteins play a key role during invertebrate differentiation but, only recently, the involvement of these proteins during vertebrate organogenesis as regulators of developmental gene expression has been confirmed. Various tissues are regulated by PRC2 during development (Table 1).
Embryonic stem cells (ESC) are able to differentiate into all derivatives of the three primary germ layers and their pluripotency is preserved by the inhibition of differentiation and the promotion of proliferation [71]. Therefore, ESC can be an extremely valuable model to study cell fate transition mechanisms involved in mammalian development. As previously explained, during development, epigenetic changes regulate the activation determining cell fate.
Genome wide analysis revealed that epigenetic changes regulate the activation or the inhibition of lineage-specific transcription factors in cell fate transition, suggesting their role in the maintenance of ESC pluripotency. For what concerns the polycomb repressive complexes, they occupy gene promoter sequences of the main developmental genes, impeding their transcriptional activation through repressive marks [44-46].
Major targets of PRC2 are tumor suppressor genes, such as Ink4b/Arf/Ink4a locus and their inhibition promotes cell proliferation [44,132,136-141].
In ESC, numerous differentiation-related genes feature a bivalent epigenetic regulation in preparation of lineage commitment [65]. This bivalent epigenetic regulation consists in the presence of both H3K27me3 and H3K4me3, which respectively are a repressing and an activating mark of transcription [142]. Upon differentiation, PRC2 complex dissociates from these gene promoters, inducing H3K27me3 removal and gene expression [45,46].
Similarly to ESC, PRC2 is involved in organ development through tissue-dependent mechanisms. As a general rule, EZH2 prevents differentiation by inhibiting genes involved in its completion. For instance, EZH2 negatively regulates skin development by repressing premature differentiation of skin progenitors. Specifically, it has been shown that in this specific differentiation model, EZH2 prevents epidermal differentiation by inhibiting the recruitment of AP1, a transcriptional activator, to Ink4/ARF locus, thus maintaining proliferative potential of epidermal progenitors [120]. Likewise, it has been reported that silencing of EZH2 in hepatic stem/progenitor cells promotes the differentiation into hepatocytes and further enhances the maturation of hepatocytes through Ink4a-Ink4b dependent and independent mechanisms [130].
EZH2 also contributes to pancreatic regeneration, by the suppression of Arf/Ink4a locus and the promotion of pancreatic β-cells proliferation, [132] and to terminal differentiation inhibition of mammary gland alveolar cells during pregnancy, in order to prevent milk production and secretion until parturition [135].
In opposition to PRC2-dependent mechanisms mentioned above, there are some tissues and organs, which require PRC2 activity for differentiation completion. For instance, recent studies showed a promoting role of EZH2 methyltransferase activity in adipogenesis. EZH2 is required, indeed, for silencing of Wnt1, -6, -10a, and -10b genes, which are inhibitors of adipogenesis [134]. Moreover, EZH2 contributes to the correct development by preventing the inappropriate gene expression, typical of different cell types. The cardiac differentiation is an example of this PRC2-dependent regulatory function; indeed, EZH2 is involved in transcriptional repression of genes as Six1, responsible of skeletal muscle genes activation in cardiomyocytes. EZH2-knockout mice feature postnatal myocardial pathologies and altered cardiac gene expression [123,125]. EZH2 promotes evenly, by indirect mechanism, liver differentiation by the inhibition of Pdx1 gene, which is involved in pancreatic differentiation promotion [133].
The complexity of PRC2-dependent molecular pathways in organogenesis has been specifically demonstrated by extensive studies in neurogenesis and myogenesis.
4.1. Role of EZH2 in neurogenesis
Neurons and astrocytes derive from common neural precursors (neuronal stem cells: NSC), which sequentially pass through phases of expansion, neurogenesis and astrogenesis. The timing of the switch from neurogenic to astrocyte differentiation is crucial for the determination of neuron numbers.
Analysis of EZH2 expression in neurogenesis showed that EZH2 decreases when NSCs differentiate into neurons and is completely suppressed in astrocyte differentiation. In contrast, EZH2 expression remains high in oligodendrocyte differentiation, from precursor cells to the immature stage [113]. EZH2 silencing and overexpression in NSCs confirmed these results, indeed forced expression of EZH2 increases the number of oligodendrocytes and reduces the number of astrocytes [113]. Furthermore, forced expression of EZH2 in astrocytes induces a partially dedifferentiation to NSCs [117], supporting a key role for EZH2 towards oligodendrocyte commitment. For what concerns EZH2 silencing, it has been reported that inhibition of EZH2 or EED in neural precursor cells extends neurogenic phase, inducing an increased production of neurons and a delay in gliogenesis [114]. However, Pereira and colleagues found that loss of EZH2 results in a shift from self-renewal towards differentiation, accelerating the timing for both cortical neurogenesis and gliogenesis [115]. These differences could be accounted to differential EZH2 inhibition timing before or after neurogenesis onset; further studies are required to clarify this pathway, but all data confirm an essential role for PRC2 in the regulation of developmental transitions timing.
4.2. Role of EZH2 in skeletal myogenesis
Proliferation and differentiation of skeletal muscle cells are controlled by a family of myogenic transcription factors, known as bHLH proteins. MyoD is one of the most important bHLH factors, which is crucial for complete muscle differentiation [143]. In ESC, PRC2 binds and represses numerous MyoD target genes [46]. In skeletal myoblasts, despite MyoD expression, PRC2 is recruited by YY1 to muscle-specific genes, inhibiting their expression and preventing premature differentiation. After the commitment of myogenesis, EZH2 expression decreases and H3K27me3 at MyoD-target loci is removed. Consequently, muscle-specific genes are transcriptionally active [126]. This process is finely regulated by miR-214, a miRNA expressed after myogenic commitment of MyoD. In myoblasts, PRC complexes occupy and repress transcription of the intronic region containing miR-214. During myogenesis decreased levels of EZH2 allow derepression of the miR-214 locus. miR-214, on the other hand, targets EZH2 3‘UTR reducing its mRNA translation, thus inhibiting EZH2 mRNA translation [88].
It has been shown that UTX, a specific demethylase that accomplish the muscle specific genes activation, is specifically involved in removal of H3K27me3 and in establishment of H3K4me3, an epigenetic marker of active genes [127].
Interestingly, EZH1 expression increases during myogenesis and its levels remain elevated in differentiated myoblasts [144]. It has been demonstrated that PRC2-EZH1 complex has a crucial role in the correct timing of transcriptional activation of muscle specific genes, as myogenin, allowing proper recruitment of MyoD on its target promoters. This mechanism involves another epigenetic modification, the phosphorylation of serine 28 of the histone H3 (H3S28ph), which is fundamental for the displacement of the PRC2-EZH2 complex [129].
This example proves the complexity of PRC2 dependent mechanism during development and demonstrates how distinctive complexes can regulates various stages of differentiation.
Despite the numerous roles of PRC2 in differentiation and organogenesis are attributable to a tissue-specific behavior, further studies are required to clarify each time its role in any process of differentiation.
It is certainly clear that both PRC2 and its catalytic subunit EZH2 can be defined as key factors in the regulation of development and in preserving cell identity.
5. EZH2 and cancer
Epigenetic abnormalities lead to altered gene expression and cellular physiology and occur in several pathologies such as cancer [145,146]. Cancer epigenetics is a branch of cancer biology that focuses on the epigenetic malfunctions involved in cancer initiation and progression [11]. EZH2 is differentially expressed in many tumors with abnormally elevated levels in cancer tissues versus the corresponding normal ones. Of interest is that EZH2 expression is generally correlated with metastatic cancer cells and poor prognosis [32].
Microarray studies in breast and prostate cancers were the first reports addressing the implication of EZH2 in tumor progression [79,147]. Currently, a wide number of human cancers associated with the deregulation of EZH2 have been discovered (Table 2).
The role of PcG proteins in cancer epigenetics is partially attributed to their contribution in transcriptional repression of INK4b-ARF-INK4a locus, which encode p15INK4b, p16INK4a and p14ARF proteins. These proteins constitute a homeostatic mechanism that protect organism from inappropriate growth signals, which would eventually lead to uncontrolled proliferation, promoting in contrast senescence or apoptosis [139]. Various tumors are characterized by mutations or transcriptional repression at INF4b-ARF-INKa locus, which is frequently a consequence of an aberrant epigenetic landscape established by factors as EZH2.
p15INK4b and p16INK4a are cyclin-dependent kinase inhibitors (CdkI) that function upstream in the retinoblastoma protein (pRb) pathway. pRb can be found in two isoforms: hypo-phosphorylated pRb is the biologically active form, while hyper-phosphorylated pRb is inactive. Hypo-phosphorylated pRb binds and inhibits E2F transcriptional factor activity. Cdks, through phosphorylation of pRb, render E2F an active transcriptional activator on the E2F target genes. INK4 proteins bind Cdk4 and Cdk6, blocking the assembly of catalytically active Cyclin–Cdk complexes.
The result of an elevated transcription of INK4 proteins is a pRb-dependent cell-cycle arrest in G1-phase [44,132,136-141,188,189]. Differently from INK4 proteins, p14ARF activates p53 pathway by inhibiting MDM2 functions. Indeed, MDM2 modulates p53 activity by inducing its transcriptional repression and by promoting its proteasome-mediated degradation. p14ARF induction generally causes cell-cycle arrest in G1 and G2 phases and apoptosis [139,190,191]. Interestingly, EZH2 activity on p16INK4a promoter is Rb family-dependent. Indeed, EZH2 is not able to bind INK4a locus in Rb proteins-deficient cells. A model has been proposed where pRb recruits PRC2 to the p16INK4a promoter, which in turn promotes its transcriptional repression [192].
EZH2 has shown a functional role evenly on pRb2/p130. pRb2/p130 is a member of Rb family that binds and recruits HDAC1 at Cyclin A promoter, inducing gene silencing. Cyclin A is a protein with a crucial role in cell cycle advancement. EZH2 competes with HDAC1 for its binding with pRb2/p130, disrupting both proteins occupancy on cyclin A promoter, inducing cyclin A activation and cell cycle progression [193,194].
As well as Rb family members, EZH2 inhibits tumor suppressor genes as p21 and phosphatase and tensin homolog (PTEN) [170,195]. For example, oncogenic stimuli in melanocytes provoke an oncogene-induced senescence, termed melanocytic nevus, which is a benign precursor of melanoma. EZH2 overexpressing cells escape senescence through the inhibition of p21. EZH2 depletion indeed, results in p21 activation and senescence induction in human melanoma cells [195]. A similar functional role has been reported in B-cell acute lymphoblastic leukemia (B-ALL) cells, where EZH2 overexpression induces p21, p53 and PTEN silencing whereas its knockdown induces cell cycle arrest and apoptosis [170].
As already stated, EZH2 is involved in apoptosis regulation [196,197]. High levels of EZH2 induce silencing of DAB2IP, a Ras GTPase-activating protein that promotes apoptosis through the tumor necrosis factor-mediated JNK signaling pathway [196], and Bim, a protein that promotes E2F1-dependent apoptosis [197].
DAB2IP is downregulated by epigenetic modifications in multiple aggressive cancers such as lung, breast and prostate. In medulloblastoma, EZH2-dependent-DAB2IP repression correlates significantly with a poor prognosis, independent by the metastatic stage [187].
Recent reports, using genome-wide technologies, reported that a large number of differentiation-related factors are PRC2-target genes [43-47]. Consequently, numerous differentiation-related factors as Gata, Sox, Fox, Pou, Pax, components of Wnt, TGF-β, Notch, FGF and retinoic acid pathways are silenced by EZH2 [32,44-46]. It has been proposed that similarly to ESC, the role of EZH2 in cancer is linked to its activity in self-renewal promotion and in the maintenance of undifferentiated state of cells; EZH2 deregulation indeed, strongly contributes to the transcriptional silencing of tumor suppressor and differentiation genes, promoting therefore uncontrolled cell proliferation and cancer progression [32]. For instance, EZH2 is upregulated in Rhabdomyosarcoma (RMS) cell lines and primary tumors [180]. RMS is a tumor that arises from muscle precursor cells, characterized by a partial myogenic differentiation. RMS cells do not form functional muscle units and feature a strong proliferative ability. Specifically, as shown in a recent study, EZH2 binds and silences several muscle gene promoters evenly under differentiated conditions. The silencing of EZH2 promotes the reduction of H3K27me3 establishment, the recruitment of elongating RNA Polymerase II at these loci and the activation of muscle specific genes, with a partial recovery of skeletal muscle phenotype [182].
Finally, PRC2 complex inhibits the expression of several tumor suppressor miRNA. For instance, downregulation of miR-31, a common event of various melanomas, is caused by epigenetic silencing of EZH2-mediated histone methylation [177].
Moreover, in metastatic liver cancers, up-regulation of EZH2 inhibits miR-139-5p, miR-125b, miR-101, let-7c, and miR-200b, promoting cell motility and metastasis-related pathways [163].
Human cancers associated with overexpression of EZH2
5.1. Extra-nuclear function of EZH2
The role of EZH2 as chromatin regulator has been extensively analyzed in a number of normal and pathological models. Recent studies demonstrated a localization of EZH2 and other PRC2 components in the cytoplasm of murine and human cells [198]. Cytoplasmic EZH2 maintains its methyltransferase activity and interacts with Vav1, a GDP-GTP exchange factor (GEF) for members of the Rho-family of GTPases. EZH2-Vav1 complex is necessary for actin reorganization and cellular proliferation in T-lymphocytes and fibroblasts, promoting cytoskeletal dynamics and cell migration as well as proliferation [198]. An example of this specific cytoplasmic function could be found in prostate cancer cells, characterized by increased levels of both nuclear and cytoplasmic EZH2. Cytoplasmic EZH2 might influence cell adhesion and migration, contributing to invasiveness and metastatic ability of tumors [199,200]. The nuclear and cytoplasmic functions of PRC2 thereby could co-operate to promote tumorigenesis.
5.2. Tumor suppressor roles of EZH2
Up to few years ago, EZH2 and PRC2 upregulation were assumed to hypermethylate H3K27, repressing the transcription of tumor suppressor genes. In 2010, Morin and colleagues identified a somatic mutation (Tyr641), which affects the EZH2 catalytic domain activity in diffuse large B-cell lymphoma but not in mantle cell or T-cell lymphoma. Specifically, mutations in lymphoma were heterozygous but haploinsufficient for the enzymatic activity, resulting in global deficit of H3K27 methylation and derepression of gene expression [168]. It has been supposed that the loss of EZH2 in lymphoma may lead to derepression of genes, promoting cell growth [201]. Other reports demonstrated that specific mutations in the EZH2 enzyme display limited capacity to carry out H3K27 monomethylation but have high efficiency for driving di- and tri-methylation. In B-cell lymphomas, mutant and wild type EZH2 co-operate increasing the trimethylated form [202].
Although the data analyzed as of now allow us to classify EZH2 as an oncogene, it must be stated that in particular cellular environments the picture becomes less clear, like for example in malignant myeloid diseases. Three different reports showed the inactivation of EZH2 in myelodysplastic syndromes (MDSs) and in myeloproliferative disorder (MPD) [203-205]. Point mutations of EZH2 gene in MDSs, MPD, and primary myelofibrosis (PMF) are predictors of poor overall survival, independently by risk factors [206,207]. Similarly, three studies conducted in T-acute lymphoblastic leukemia (T-ALL) demonstrated that PRC2 displays a tumor suppressor role in this pathology [171,208,209]. Particularly, Simon and colleagues demonstrated that in mouse, loss of EZH2 in hematopoietic stem cells induces aggressive T-ALL. Similar studies in human showed a comparable decrease of EZH2 levels in T-ALL [171]. Moreover, Ntziachristos and coworkers found that EZH2 and other PRC2 core components are frequently mutated in T-ALL samples [209]. Of interest is that the frequency of PRC2 mutations is higher in pediatric subtype of leukemia [208].
Despite mutations of EZH2 seem specific for a few type of cancers, latest reports suggest a fine balance of H3K27 methylation, necessary for normal cell growth. Recent studies showed an indirect EZH2-dependent mechanism involved in pancreatic cancer inhibition. Jon Mallen-St. and co-authors investigated the role of EZH2 in pancreatic regeneration and in cancer progression using a mouse model characterized by KRas activation, frequently mutated in pancreatic tumors. In particular, they show that KRas mutated mice developed preneoplastic lesions but rarely progressed into invasive adenocarcinoma. The loss of EZH2 function in this experimental model increases by 6 times the development of pancreatic intraepithelial neoplasia, suggesting a protective role of EZH2 in pancreatic carcinogenesis. Since EZH2 is transiently upregulated after injury and returns to basal levels after tissue recovery, it has been proposed that, in injured tissue, surviving acinar cells de-differentiate into metaplastic epithelial intermediates are able to proliferate and restore pancreatic injury. Proliferation is induced by EZH2 activation through P16INK4a inhibition. Subsequently, acinar cell mass and function is finally restored through re-differentiation, which corresponds to restored basal levels of EZH2. EZH2 is involved therefore in homeostatic mechanisms that controls pancreatic regeneration, decreasing the risk of pancreatic cancer in patient with chronic pancreatic injury [156,184].
6. Conclusions
Epigenetic alterations in cancer cells represent an important aspect of tumor biology. Differently from genetic modifications, epigenetic alterations can be reversed by specific drugs inducing the restoration of “normal” cellular pathways, which in turn promote cellular senescence or apoptosis. Therefore, epigenetic changes are excellent target candidates for chemotherapeutic intervention in cancer.
Several HDAC and DNMT inhibitors are already available as putative anticancer drugs, and several clinical trials are underway [210,211].
A pharmacological therapy, which specifically targets EZH2, may constitute a novel approach to the treatment of cancer, assuming its role in inhibition of several tumor suppressor or differentiation genes.
Recently, an S-adenosyl-L-homocysteine (AdoHcy) hydrolase inhibitor, 3-Deazaneplanocin A (DZNep), has been demonstrated to deplete EZH2 and remove H3K27me3 at PRC2 target genes. The inhibition of AdoHcy hydrolase fosters accumulation of AdoHcy, which in turn stops S-adenosyl-L-methionine (SAH)-dependent methyltransferases.
DZNep promotes apoptosis in cancer cell lines as breast and colorectal cancer cells, but not in normal cells. DZNep reduces cellular levels of PRC2 subunits, inhibits H3K27 methylation and promotes the reactivation of PRC2 silenced genes and apoptosis [212]
Of interest is that, in several non-small cell lung cancer (NSCLC) cell lines, DZNep treatment results in p27 accumulation, G1 cell cycle arrest and apoptosis, whereas immortalized bronchial epithelial and fibroblast cell lines are less sensitive and show apoptosis with lesser extent, which render it a potential candidate in anti-cancer therapy [160].
Studies in various gastric cancer cell lines and in primary human gastric cancer cells showed that the DZNep responsiveness is attenuated in p53-depleted cells. p53 genomic status is therefore a potential predictive marker of DZNep response in this specific cell type [213].
Despite its potential usefulness in cancer therapy, further studies need to address its target specificity. Indeed, it has been reported that DZNep inhibits H4K20 methylation, another epigenetic modification, which is involved with chromosome stability [212]. The effect of DZNep on several methyl transferases activity is a strong limiting factor for its use as anti-cancer drug.
New PRC2 targets have been recently developed. GSK126 is a small molecule, competitor of S-adenosyl-L-methionine. Unlike DZNep, that reduce levels of EZH2 indirectly, GSK126 specifically inhibits EZH2 methyltransferase activity with no alterations in EZH2 expression. In lymphoma cells, GSK126 treatment decreases global H3K27me3 levels and reactivates PRC2 target genes. [169]. Finally, it has been discovered a natural compound, 16-hydroxycleroda-3,13-dien-15,16-olide (PL3), which is able to promote apoptosis in leukemia K562 cells by the modulation of various histone-modifying enzymes among which EZH2 and SUZ12 [214].
Other studies are needed to design inhibitors specific for PRC2 and to develop new strategies for epigenetic therapy in cancer.
Acknowledgments
We are grateful to Dr. Francesco Paolo Fiorentino for his helpful comments on this manuscript.
This work was supported by a grant from POR FSE 2007–2013 “Regione Autonoma della Sardegna, Programma Master and Back” and a grant from “Fondazione Banco di Sardegna” (Rif. Vs Prot. 469/2011.271).
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Introduction",level:"1"},{id:"sec_2",title:"2. PcG proteins and PRC-mediated silencing",level:"1"},{id:"sec_3",title:"3. Regulation of PRC2 activity",level:"1"},{id:"sec_3_2",title:"3.1. Regulation of PRC2 components expression",level:"2"},{id:"sec_4_2",title:"3.2. Post-translational modification of EZH2",level:"2"},{id:"sec_5_2",title:"3.3. PRC2 recruitment to target genes ",level:"2"},{id:"sec_7",title:"4. Role of PRC2 in differentiation and cell fate commitment ",level:"1"},{id:"sec_7_2",title:"4.1. Role of EZH2 in neurogenesis",level:"2"},{id:"sec_8_2",title:"4.2. Role of EZH2 in skeletal myogenesis",level:"2"},{id:"sec_10",title:"5. EZH2 and cancer",level:"1"},{id:"sec_10_2",title:"5.1. Extra-nuclear function of EZH2",level:"2"},{id:"sec_11_2",title:"5.2. Tumor suppressor roles of EZH2",level:"2"},{id:"sec_13",title:"6. 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Cancer DNA Methylation: Molecular Mechanisms and Clinical Implications. Clinical Cancer Research 2009;15(12): 3927–37. '},{id:"B160",body:'Kikuchi J, Takashina T, Kinoshita I, Kikuchi E, Shimizu Y, Sakakibara-Konishi J, et al. Epigenetic therapy with 3-deazaneplanocin A, an inhibitor of the histone methyltransferase EZH2, inhibits growth of non-small cell lung cancer cells. Lung Cancer 2012;78(2): 138–43. '},{id:"B161",body:'Mimori K, Ogawa K, Okamoto M, Sudo T, Inoue H, Mori M. Clinical significance of enhancer of zeste homolog 2 expression in colorectal cancer cases. European Journal of Surgical Oncology 2005;31(4): 376–80. '},{id:"B162",body:'Sudo T, Utsunomiya T, Mimori K, Nagahara H, Ogawa K, Inoue H, et al. Clinicopathological significance of EZH2 mRNA expression in patients with hepatocellular carcinoma. British Journal of Cancer 2005;92(9): 1754–8. '},{id:"B163",body:'Au SL-K, Wong CC-L, Lee JM-F, Fan DN-Y, Tsang FH, Ng IO-L, et al. 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'},{id:"B203",body:'Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV, et al. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nature Genetics 2010;42(8): 722–6. '},{id:"B204",body:'Nikoloski G, Langemeijer SMC, Kuiper RP, Knops R, Massop M, Tönnissen ERLTM, et al. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nature Genetics 2010;42(8): 665–7. '},{id:"B205",body:'Makishima H, Jankowska AM, Tiu RV, Szpurka H, Sugimoto Y, Hu Z, et al. Novel homo- and hemizygous mutations in EZH2 in myeloid malignancies. Leukemia 2010;24(10): 1799–804. '},{id:"B206",body:'Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G, et al. Clinical Effect of Point Mutations in Myelodysplastic Syndromes.The New England Journal of Medicine 2011;364(26): 2496–506. '},{id:"B207",body:'Guglielmelli P, Biamonte F, Score J, Hidalgo-Curtis C, Cervantes F, Maffioli M, et al. 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Journal of Biomedicine and Biotechnology 2011; doi:10.1155/2011/475641 '},{id:"B212",body:'Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL, et al. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes & Development 2007;21(9): 1050–63. '},{id:"B213",body:'Cheng LL, Itahana Y, Lei ZD, Chia NY, Wu Y, Yu Y, et al. TP53 Genomic Status Regulates Sensitivity of Gastric Cancer Cells to the Histone Methylation Inhibitor 3-Deazaneplanocin A (DZNep). Clinical Cancer Research 2012;18(15): 4201-12. '},{id:"B214",body:'Lin Y-H, Lee C-C, Chang F-R, Chang W-H, Wu Y-C, Chang J-G. 16-Hydroxycleroda-3,13-dien-15,16-olide regulates the expression of histone-modifying enzymes PRC2 complex and induces apoptosis in CML K562 cells. Life Sciences 2011;89(23-24): 886-95. '}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Irene Marchesi",address:null,affiliation:'
Department of Biomedical Sciences, Division of Biochemistry and National Institute of Biostructures and Biosystems, University of Sassari, Sassari, Italy
Department of Biomedical Sciences, Division of Biochemistry and National Institute of Biostructures and Biosystems, University of Sassari, Sassari, Italy
Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, USA
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1. Introduction
Citrus fruits are the most predominantly produced fruits worldwide. The citrus species, Rutaceae family, is one of the major fruit crops in the world, which has provided an immune-enhancing source of vitamin C, nutrients, and medicinal value since ancient times [1]. Citrus crops are cultivated in more than 135 countries worldwide [2]. Worldwide citrus production is estimated at over 124.3 million tons annually [3]. Cultivated commercial citrus plants, consisting of rootstock and scion varieties, have a significant impact on scion growth, fruit quality, yield, and tolerance to biotic and abiotic stresses [4, 5]. Therefore, the selection of rootstock may make a significant contribution to the success or failure of the planting process [2]. However, various biotic and abiotic stresses impede citrus production worldwide, among which Huanglongbing is one of the significant pernicious diseases devastating the citriculture industry in the last few decades. Citriculture industries in Asia, Africa, and America have suffered massive economic losses due to the devastating Huanglongbing (HLB) malady [6].
Citrus HLB (Yellow dragon disease or citrus greening) is one of the highly ruinous diseases in citrus species caused by proteobacteria Candidatus Liberibacter species. The casual organisms of HLB have not been successfully cultured on axenic culture to date, and the prevalence of the HLB pathogen in citrus plants was evaluated using a diagnostic polymerase chain reaction (PCR) technique. Diaphorina citri Kuwayama (Asian citrus psyllid (ACP)) and Triozaerytreae (African citrus psyllid (AfCP)) transmit HLB disease from one citrus plant to another and also feed on many other species of the Rutaceae family [7]. The ACP resides in warm and humid zones and is most prevalent in Asia, the Indian subcontinent, Saudi Arabia, Reunion, and Mauritius. Now, ACP has also spread to South and Central America, such as Brazil, USA, and Mexico [8]. AfCP thrives in cold weather and is sensitive to the sweltering climate. AfCP resides in Africa, Cameroon, South Africa, Yemen, Madagascar, and Madeira Island [9]. HLB was first identified as a significant issue of unknown disease in citrus by farmers in southern China at the end of the nineteenth century [10]. HLB was first known a century ago as Citrus “Dieback” in India and “Yellow Dragon shoot Disease” in China, with a clear impact on citrus production in many countries, followed by South Africa, the Philippines, Indonesia, Thailand, Brazil, and the United States [11].
Citrus are susceptible to HLB, that is, nearly all commercial citrus and some citrus relatives. Poncirus trifoliate citrus, some P. trifoliate hybrids, and a few lemon varieties are considered more HLB tolerant [12]. The most efficient and sustainable strategy against citrus HLB is breeding resistant citrus cultivars. However, conventional citrus breeding is a long-term process that takes about 20 years to develop a new variety. Further, breeding efficiency is affected by gametophytic cross-incompatibility, heterozygosis, pollen-ovule sterility, apomixis, seedlessness, graft incompatibilities, polyembryony, and unstable characteristics [13]. Genetically engineered resistant citrus varieties are yet to be available for commercial cultivation due to the lack of acceptance of GMOs from farmers and consumers. It will, therefore, take many years to develop a promising resistant cultivar against HLB [14].
Many strategies to combat HLB were initiated, such as thermotherapy, antibiotics, plant defense initiators, pesticide, vector control management, chemotherapy, nanotechnology, and a transgenic approach [15, 16]. Beta-lactams, tetracyclines, and silver nanoparticles have obtained better results against HLB malady [17, 18]; however, the emergence of antibiotic resistance to microorganisms and indirect effects on human health and the environment is a significant and increasing risk that certainly restricts the use of antibiotics at the field level [18]. However, no effective strategies to eliminate or repress the HLB pathogens have been identified. This review attempts to provide an overall picture of HLB disease, distribution, casual organism and its pathogenic mechanism, and vector control management, and post the current and possible strategies to mitigate/combat HLB malady in the field.
2. Incidence, distribution, symptomology, and detection of citrus Huanglongbing
2.1 Incidence of Huanglongbing
HLB (also known as Yellow Dragon/shoot disease) was first identified as an unknown disease in citrus trees by citrus farmers in Guangdong Province, China, at the end of the nineteenth century [19], but studies suggest that HLB most likely originated in Taiwan in 1870 where it was known as Likubin (“Drooping disease”) [20, 21]. Later, the HLB spread to other parts of China; by 1935, it had become a severe disease of citrus species [21]. Like HLB, dieback was first described in the central parts of India in the middle of the eighteenth century [22]. At that time, it might have been limited, but HLB was recorded in Assam in the eighteenth century and, by 1912, was a devastating disease in Bombay, India. However, the Citrus tristeza virus might cause this disease. Raychaudhuri [23] exhibited that dieback was the same as HLB. African greening disease was first identified in a sweet orange orchard in parts of South Africa in 1929 [24]. Outside of China, HLB was known as the “Greening” disease in South Africa, where extensive research was conducted in the 1950s. In Indonesia, the HLB disease was first noticed in the 1940s and is called the “citrus phloem degeneration” disease [25]. Reinking, in 1919, first described this disease in English as yellowing and leaf mottle of citrus noticed in China. According to International nomenclature rules, the name “Huanglongbing” was considered the official name by citrus pathologists at the 13th conference of the International Organization of Citrus Virologists in China [26]. “Huanglong” means yellowing of the shoot, as well as the yellow dragon (the symptom appears almost like a yellow dragon over the infected trees) and “bing,” which means disease in Chinese [10]. Since the discovery of HLB, it has been named differently worldwide [27]. HLB was known outside under the name “citrus dieback” in India [23], “mottle leaf disease” in the Philippines [28], “vein phloem degeneration disease” in Indonesia [25], “yellow branch,” “blotchy mottle,” or “greening” disease in South Africa [29].
2.2 Geographical distribution
Globally, HLB has been considered one of the significant threats to citrus commercial and sustainable production. HLB was confirmed in citrus-producing regions of various countries, such as Nepal, Bangladesh, Thailand, Pakistan, Japan, Vietnam, Cambodia, Laos, Malaysia, Central African Republic, Comoros, Ethiopia, Kong Hong, Kenya, Madagascar, Malawi, Mauritius, Saudi Arabia, Reunion, Rwanda, Yemen, Zimbabwe, Somalia, Tanzania, Swaziland, and various region of United States of America including California, Florida [7, 27]. HLB has been reported in 24 countries and territories in East, South, Southwest Asia, East, and South Africa. Since then, it has been widely spread in other Asian, American, and African countries [27].
2.3 Symptomology
HLB symptoms are more evident in cold weather conditions than in hot seasons [30]. It is difficult to specify the period between when the citrus tree is affected by HLB and the onset of disease symptoms. It will exhibit in different parts of the plants or only in infected sectors when it eventually manifests symptoms. It is, therefore, difficult to diagnose and control at the early stage of HLB disease [31]. The HLB-infected tree exhibits symptoms in various parts of the plant depending on the stage of infection. If infection occurs soon after propagation, the entire tree gets affected and turns yellow all over the canopy, which leads to a decline irrevocably. Both the symptoms and the causative organisms were restricted to the infected sector in the event of later infection [27]. Only the infected sector will exhibit symptoms in the case of citrus trees affected by HLB, while the remaining parts will show normal growth and good-quality fruits. The symptoms observed on the HLB-affected tree include a heavy drop in the leaf and out-of-season flushing and blooming. Chronically, HLB-affected trees displayed stunting growth, twig dieback, sparse yellow foliage, or severe fruit drop [24]. The initial stage of HLB is vein yellowing [32], and the secondary level includes (infected leaves) small, upright with various chlorotic patterns similar to that caused by nutrient deficiency, such as zinc, sulfur, iron, boron, manganese, and calcium [33, 34]. In severe cases, the leaves were utterly void of chlorophyll, except for rounded green spots located on the leaves at random places [24]. The most accurate diagnostic symptom for HLB is that the infected fruits are small, lopsided, and taste bitter and salty. HLB-affected trees with premature shedding of green fruit drops while remaining on the tree, in which fruits with yellow halo-like lesions were staying green on the shaded side, hence the name “greening” [7, 34]. Root systems are developed in severely infected trees that exhibit poorly formed roots with few fibrous roots due to undernourishment [24] and repression of new root growth and rootlets decay [10].
HLB disease is challenging to diagnose based on symptoms, particularly during the early stages of the disease. Numerous symptoms of HLB might occur, and citrus trees are often caused by other diseases or nutrient deficiencies that may lead to similar symptoms [11, 30, 35]. Symptoms could be aggravated by other pathogens being coinfected. Several reports from Asian countries postulated that HLB-affected citrus trees are commonly coinfected with the Citrus tristeza virus (CTV) [7]. Interestingly, some CTV isolates protect trees against HLB infection [36]. Blotchy mottle leaf is a principal diagnosis of HLB that could be misinterpreted with other diseases, such as stubborn citrus disease caused by Spiroplasma citri, a severe infection of CTV phytophthora root rot, zinc deficiency, and waterlogging. Furthermore, it can also be confused with symptoms of leaf-related stress and mineral deficiency [37]. Early stages of citrus blight are also associated with the symptoms of zinc deficiency [38]. For these confusing symptoms of the disease, an unequivocal diagnosis technique is needed for HLB disease.
2.4 Method of HLB detection
Early identification and isolation of Canditatus Liberibacter species-infected trees are effective management approaches used to limit the spread of HLB from invading HLB disease-free citrus orchards in local and international trade [39]. Visual examination is one of the most commonly employed approaches for detecting citrus HLB disease. Traditionally, early detection of HLB disease relied primarily on various symptoms in the field, such as blotchy mottle leaf, yellow shoot, aborted seed, and lopsided fruit with green color remaining at the stylar end [40]. Nevertheless, this approach is highly affected by subjective interpretation, diagnostic errors can be higher than 30%, and other biotic and abiotic stress-related problems may worsen diagnosis. HLB symptoms might be confused with diseases such as Citrus Tristeza Closterovirus, Phytophthora infection, citrus blight, and specific nutrient deficiencies [41]. Thus, the availability of advanced technologies that enable early and rapid detection of HLB pathogens is crucial [42]. Currently used methods for the diagnosis and confirmation of HLB disease include serology, enzymatic assay, enzyme-linked immunosorbent assays (ELISA), transmission electron microscopy, DNA probes, conventional polymerase chain reaction (PCR), quantitative PCR (qPCR), Fourier transform infrared spectroscopy (FTIR), and mid-infrared spectroscopy. Pereira et al. [43] developed a method for early diagnosis using X-ray fluorescence. The laser-induced breakdown spectroscopy (LIBS) combined with chemometric strategies is used to predict the condition of orchard plants infected with Canditatus Liberibacter species successfully. However, these methods did not provide early diagnosis except for the LIBS method. Recently, Tran et al. [44] reported a sensitive and selective label-free biosensor that combines the physical and chemical advantages of carbon nanomaterials such as single-walled carbon nanotubes (SWNTs) in a field-effect transistor (FET)/chemiresistor architecture with selective antibodies against Sec-delivered effector 1 (SDE1), a secreted protein biomarker, for the detection of HLB. Detailed HLB detection techniques have recently been reviewed [42, 45].
3. Causal agents of citrus Huanglongbing
The bacterium associated with citrus HLB was Candidatus Liberibacter species, which belongs to the alpha-proteobacteria determined by the 16 s ribosomal DNA sequences and the operon [9]. Proteobacteria associated with HLB disease in citrus are successively referred to as Candidatus Liberibacter asiaticus (Las) found in the majority of HLB-affected countries, Candidatus Liberibacter africanus (Laf) limited to African countries, and Candidatus Liberibacter americanus (Lam) limited to America [15]. How Candidatus Liberibacter bacterium established its association with citrus species remains unclear.
Scientific classification of Candidatus Liberibacter.
Kingdom: Bacteria.
Phylum: Proteobacteria.
Class: Alphaproteobacteria.
Order: Rhizobiales.
Family: Rhizobiaceae.
Genus: Candidatus Liberibacter.
3.1 In vitro culture of Candidatus Liberibacter species associated with HLB
The isolation of Candidatus Liberibacter species, causing HLB in an artificial culture medium, was a primary target for many researchers. Davis et al. [46] attempted to isolated Candidatus Liberibacter asiaticus in a culture medium from young angular green shoots from HLB-affected trees. A growth film appeared on the bottom of the tube containing broth AD medium. After single-colony isolation, Las and the actinobacteria closely related to Propionibacterium acnes remained together. Thus, Las was not isolated in axenic culture. Moreover, actinobacteria are prevalent residents of citrus and psyllids, whether Las is present. Sechler et al. [47] successfully cultivated a single colony of all three Candidatus Liberibacter species from HLB-affected leaf midveins and petiole sap in a new medium designated Liber A. The isolated cells were ovoid to rod-shaped, 0.3 to 0.4 by 0.5 to 2.0 μm, often with fimbriae-like appendages. They isolated two Las and one Lam strains from non-inoculated tissues of inoculated trees and seedlings 9 and 2 months later.
3.2 The pathogenic mechanism of Candidatus Liberibacter
Candidatus Liberibacter species are gram-negative, phloem-restricted bacterium associated with the pernicious disease of citrus HLB. Although Candidatus Liberibacters have been cultivated in artificial media, traditional molecular and genetic analyses have been difficult to perform owing to declining viability in culture [46, 48]. This difficulty has significantly limited efforts to comprehend the mechanisms of Liberibacter virulence. To date, most insights into the mechanisms of Liberibacter pathogenesis have been acquired through genomic analyses of Liberibacter sequences, host plant transcriptomic, proteomic, and metabolomic data associated with Liberibacter infection, and studies involving surrogates such as Sinorhizobium and E. coli, and expression in planta [15]. Evidence suggests that Liberibacters species associated with HLB live solely within the phloem tissues of host citrus plants [15]. Las bacterium resides inside a sieve tube and companion cells [47, 49]. The relatively consistent symptomology among various symptom-expressing hosts is one of the hallmarks of diseases caused by Liberibacter species [15].
3.2.1 Liberibacter secretion system and effector protein
The secretome of a pathogenic bacterium represents an array of molecules that play offensive roles during colonization, among which effectors are an important class of proteins capable of suppressing defense and/or manipulating host physiology [50, 51]. Interestingly, Las contain type I secretion systems (T1SSs) and a complete general secretory pathway (Sec), but lack other secretion systems (T2SS and T3SS) [15, 52], which play a significant role in extracellular pathogenic attacks on plant and animal host [16].
Liberibacter genome analyses found a complete T1SSs system in Las and Laf, but not in Lam [15]. Genes encode for serralysin and hemolysin; a T1SSs effector protein has been identified in Las and Laf genomes [53]. Serralysin is a metalloprotease secreted by gram-negative bacteria to inactivate peptides and antimicrobial proteins produced by the host plant. Las bacterium might use serralysin to degrade antimicrobial proteins in the host as its defense mechanism. This degraded protein is used for growth and metabolism by the Las bacterium as a carbon and nitrogen nutrient [16]. On the other hand, the hemolysin gene has been identified in all sequenced Liberibacters, which play an essential role in bacteria survival in the host plant. Las-produced hemolysin triggers ion leakage and water molecules from the host cell that lead to host cell apoptosis [16, 54].
The Secretary pathway (Sec) or Sec-translocon facilitates these effector proteins’ transports outside the cytoplasm membrane vital for bacterial viability. The Sec machinery also secretes essential virulence factors in some plant-pathogenic bacteria [15]. Candidatus Liberibacter species have a general secretory pathway, which may lead to the secretion of effector proteins [55]. Since Candidatus Liberibacter species are phloem-resided bacteria, there is an inference that the bacteria secrete effector proteins directly into the cytoplasm of the host cells and modulate their physiology [56]. The effector protein CLIBASIA_05315 was located in transgenic citrus chloroplasts, resulting in leaf chlorosis and plant growth retardation [57]. Several research groups are currently focusing on identifying and characterizing the effector proteins of Candidatus Liberibacter species, and it is expected that we will have an improved view of this pathogenic mechanism of bacteria in a few years.
3.2.2 Lipopolysaccharides
Lipopolysaccharides (LPS), also known as endotoxin, are critical components derived from the outer membranes of gram-negative bacteria consisting of lipid A, an oligosaccharide core, and an O-antigen. LPSs are involved in outer membrane functions that are crucial for bacterial growth, survival against antimicrobial chemicals, and virulence, particularly within a host-parasite interaction. Lipid A is highly conserved, then the oligosaccharide core and O-antigen [15, 16]. LPSs are classical activators of defense responses in plants during plant-pathogen interaction [58]. Las bacteria use gene encoding active salicylate hydroxylase (SahA) to degrade salicylic acid (SA) and suppress plant defense mechanism. Intriguingly, the SahA gene is highly expressed in planta, while it is not expressed in psyllid vectors [56]. Las impedes SA-mediated defense responses in the phloem using its SA hydroxylase and maintains significant bacterial titer in citrus HLB disease progression over several years before the tree irrevocably declines. It is yet to be determined whether LPSs of Liberibacter cause callose accumulation in the phloem.
3.2.3 Flagella
The bacterial flagellum organelle, an intricate multiprotein essential for its rotational propulsion, promotes host colonization through adherence and induces plant immune modulation [15]. Las flagella have been reported to trigger host plant defense in planta as a pathogen-associated molecular pattern (PAMP) [59]. Microscopic studies found that flagella have not been observed in the Candidatus Liberibacter species that reside in the phloem in HLB-infected samples [11]. Despite the small size of the genome, genes associated with flagella biosynthesis have been identified in the sequenced Liberibacter genome [15, 16, 51, 52]. The genes fliF, flgI, and flgD expressed in flagellar assembly and the motB gene associated with the motor function were overexpressed in planta.
The flbT, an essential flagellin regulatory protein that acts as a regulatory checkpoint for flagellin gene expression, is found in the Las bacterial genome, whereas it is not in the Lam genome. The absence of flbT in the Lam genome results in no PAMP activation in planta [60]. Conversely, flgL, flgK, and fliE were overexpressed in psyllid [61].
3.2.4 Prophages
Several pathogenic bacteria harbor prophages or phage remnants integrated into their genome, encoding lysogenic genes that are proven or suspected virulence factors [59]. Las- and Lam-sequenced genome contains two potential prophages, Type 1 represents prophage SC1, and Type 2 represents prophage SC2. SC1 involved in the lytic cycle of forming phage particles. SC2 was implicated in the lysogenic conversion of Las pathogenesis [60, 62]. Type 3 prophage (P-JXGC-3) was identified in Las samples collected from Southern China. This prophage carries another bacterial defense system, such as a restriction-modification system (RM system) [63]. This RM system is fortified with endonucleases, which cleaves invading DNA that protects host DNA by altering specific sequences [64]. Type 1 and Type 2 prophages were not detected in the Las strain from Southern China. It is not clear whether these strains contain prophages or have unknown prophages. There are no comprehensive studies to describe the Las prophage repertoire [65]. Among strains observed in an extensive survey of Las isolates in China, it was typical for Las to have a single prophage, with Guangdong isolates harboring mainly the type 2 prophage, whereas isolates from Yunnan are dominated by the type 1 prophage [65]. The Las strain genome from Japan does not contain prophages [56]. Among the Las whole-genome sequences recently reported from different geographic areas around the globe, eight Las genomes contain extensive prophage sequences [63]. A survey of prophage prevalence in southern China revealed active prophage-phage interactions in the Las bacterial strains [63]. The exact function of the RM system has yet to be experimentally determined in Type 3 prophages. However, the lack of a prophage in many Las strains does not relate to the lack of HLB symptoms because Ishi-1 and the Guangdong isolates, which do not contain any prophages, induce similar HLB symptoms as isolates containing prophages [54, 65]. Overall, this evidence suggests that prophages contribute to bacterial virulence but are not required for Las pathogenicity.
3.3 Phloem dysfunction of HLB-affected citrus
Las bacteria reside within phloem and colonize sieve tubes [15, 16, 66]. Phloem dysfunction is a primary modification due to hyperactive differentiation of vascular cambium and hypertrophy of parenchyma cells surrounding the necrotic phloem pocket that may determine the development of HLB symptoms [32, 67]. HLB-associated Liberibacter secretes virulence factor and Sec-dependent effectors (SDEs) into phloem that stimulates HLB symptoms by interfering with either phloem or companion cell protein and genes of the host [15]. The secreted SDEs and virulence factors may interact with plastids, mitochondria, vacuole, and endoplasmic reticulum in the host phloem and target host genes and proteins to promote pathogen growth and disease development and suppress host immune responses [15]. Eventually, it leads to phloem malfunction in the host plant due to the Liberibacter virulence factors and SDE effects on sieve tubes and companion cells, which provide protein and transcripts to the sieve elements. Necrotic phloem was found in the HLB-infected plants due to starch (Figure 1) and callose deposition [32]. Callose accumulation was observed in sieve plates of Las-infected citrus [67]. Phloem dysfunction is generally associated with phloem sieve elements plugged with extensive deposition of callose and phloem protein 2 [67, 68], followed by phloem cell wall distortion and sieve element collapse [69]. Subsequently, photoassimilate transport was significantly blocked due to necrotic phloem [15, 16, 66, 68], which might result in substantial quantities of starch particles in almost all living cells of aerial parts, including phloem parenchyma and the sieve tube elements [32, 70]. The excessive accumulation of starch and zinc deficiency in chloroplast disrupts the thylakoid resulting in nonuniform loss of chlorophyll that triggers noticeable blotchy mottle appearance in the HLB-infected leaves [40, 70, 71]. The anatomical transverse section of HLB-infected leaf midrib exhibited phloem collapse with cell wall distortion and thickening in Valencia sweet orange and SB siblings [72]. In addition, hyperactive vascular cambium regenerates new phloem in the HLB-infected trees, consisting of assemblies of sieve elements, companion cells, and phloem parenchyma cells, but lacks phloemic fibers [72].
Figure 1.
SEM micrographs of transverse section of healthy and HLB-infected citrus petiole. A and B. Healthy plant; C and D. HLB-infected plants.
In addition to anatomical changes, several metabolic imbalances and genetic reprogramming are noticed in HLB-affected plants [57, 66]. Salicylic acid and downstream signaling play a key role in provoking plant defense mechanisms against biotrophic pathogens [73, 74]. Wang and Trivedi postulated that a protein with potential salicylate hydroxylase activity might convert salicylic acid into catechol [75]. Salicylic acid pathway depression was observed in HLB-susceptible citrus plants [76]. Based on the Candidatus Liberibacter and plant interactions mechanism literature, we suggest the pathogenic mechanism of Candidatus Liberibacter species associated with citrus HLB in the following model (Figure 2).
Figure 2.
Illustration of Candidatus Liberibacter virulence mechanisms in the plant.Candidatus Liberibacter species associated with HLB (red circles) live in phloem elements. Phloem is mainly liable for the distribution of the carbohydrate from the source to the sink. Nutrients are transmitted to the phloem either through the apoplastic pathway or the symplastic pathway. Candidatus Liberibacter species may secrete effector protein (sec-dependent effectors) and virulence factors (orange and blue circle, red triangles) into phloem sieve elements and companion cells to interfere with host target (genes and protein) that can cause cell necrosis, cell death, and phloem malfunction. Effectors or virulence factors may interfere with phloem organelles, such as mitochondria, plastids, or endoplasmic reticulum, to trigger cellular responses. Some effectors (SDEs) may directly or indirectly affect the expression of target genes. In addition, Candidatus Liberibacter species may trigger plant immune responses through pathogen-associated molecular patterns leading to cell death and callose accumulation, resulting in inhibition of phloem transportation. The presence of Candidatus Liberibacter species and its metabolic activity may interfere with the function of the phloem by interrupting the osmatic gradients and integrity of phloem transportation. Abbreviations: PMPs—Pathogen-associated molecular patterns; RFO—Raffinose family oligosaccharide.
4. Transmission of citrus HLB
The graft transmitted HLB was due to a viral disease [77]. Soon afterward, similar opinions were put forward in South Africa, strengthened by the results of grafting trials showing that greening was inconsistently transmitted to healthy plants. Lin [21] confirmed that HLB was transmitted through grafting in China, thus establishing the causative agent as a pathogen. McClean and Oberholzer [78] confirmed the graft transmissibility of African greening in 1965. The pathogen is not easily transmitted to progeny trees propagated by buds from infected trees, possibly due to sieve tube necrosis and uneven pathogen distribution, but more transmission occurs if stem pieces are used. No infection could be obtained when material from apparently healthy sectors of diseased trees was used. In 1964, natural spread by exposing seedlings to insects in a HLB-affected orchard developed yellowing symptoms similar to greening [79].
Two insect vectors are responsible for the rapid transmission of citrus HLB from Las-infected citrus to healthy citrus species, Asian citrus psyllid D. citri in Asia and America, and the African citrus psyllid, Triozaerytreae in Africa. The acquisition feeding period is 30 min or longer, and the pathogen remains latent for 3–20 days. The inoculation feeding period is 1 hour or more [80].
Asian citrus psyllid is widespread around the world and found in hot and humid conditions and lower-lying areas in China, India, Myanmar, Taiwan, Philippine Islands, Malaysia, Indonesia, Sri Lanka, Pakistan, Thailand, Nepal, Ryukyu Islands (Japan), Afghanistan, Saudi Arabia, Reunion, and Mauritius [81]. Asian citrus psyllid firstly evolved in India [82], then spread in South America in the 1940s, invading Brazil, Argentina, and Venezuela, and then invaded the West Indies (Guadeloupe), Abaco Island, Grand Bahama Island, Cayman Islands, and the USA in the 1990s. In 2001, ACP was found in the Dominican Republic, Cuba, Puerto Rico, and Texas [83, 84]. Asian citrus psyllid has been reported more recently in many new Americas, including Mexico, Costa Rico, Belize, Honduras, and the states of Alabama, Arizona, California, Georgia, Louisiana, Mississippi, and South Carolina, USA [85].
African citrus psyllid (AfCP) thrives in cool and moist temperatures, at higher areas about 100 to 500 m above sea level. And it is sensitive to excessive heat and exists in Africa from the islands of the Indian Ocean through east and central Africa to South Africa, Saudi Arabia, Yemen, the northwestern region of the Iberian Peninsula, Cameroon, Kenya, Ethiopia, Zimbabwe, Tanzania, Malawi, Galicia, northern Portugal, Swaziland, Madagascar, Rwanda/Burundi, and Reunion [86]. Psyllid populations in Africa, Saudi Arabia, and Yemen might be able to adapt and settle under a wide range of environmental conditions, such as equatorial, arid, and warm temperate climates with varying temperatures and rainfall [86].
5. Current strategies to combat citrus HLB
5.1 Vector control
5.1.1 Biocontrol of vector
Biocontrol uses natural enemies by import, augmentation, and conservation to control the population density of disease pathogens or pests in agriculture [87]. Asian citrus psyllid (Diaphorinacitri) was controlled using a practical method of import (from Asia) and free of Tamarixia radiata in Florida citrus groves [88]. Natural enemies, Diaphorencyrtus aligarhensis and Tamarixia radiata, were imported from Taiwan and Vietnam to Florida citrus orchard and released as a biocontrol agent for D. citri [89]. T. radiata became more widely established parasitoid wasps than its counterpart D. aligarhensis. In urban and suburban regions, the release of T. radiata could considerably benefit commercial citrus growers by reducing latent psyllid populations and preventing the further spread of HLB disease [87]. T. radiata has been firmly established in commercial citrus-producing countries, including Réunion Island [90], the Philippines [91], Indonesia [92], Guadeloupe [93], and the USA [94], where it is spread throughout the state [88]. It appeared inadvertently in Brazil, Venezuela, Mexico [95], Puerto Rico [83], and Texas [31].
In addition to wasps, many insects native to Florida are recognized as D. citri predators, including several ladybeetle and spiders [81]. Cyclonedas anguinea, Harmonia axyridis Pallas (Coccinellid beetles), and Olla v-nigrum Mulsant were the leading killer of nymphal psyllids. In addition to Ceraeochrysa, Hibanavelox (becker), spider, and Chrysoperla rufilabris Burmeister (lacewings), Tamarixia radiata (parasitoid) also contributed to the additional mortality in Florida citrus groves. Coccinellid beetles are considered one of the most important natural enemies of D. citri populations in central Florida. Besides this, intraguild predation (IGP) causes more than 95% of immature T. radiate mortality [96]. Van den Berg et al. [97] noted that the spiders are the critical predators of T. erytreae, followed by chrysopids, coccinellids, syrphids, hemerobiids, Hemiptera, and predatory mites in citrus groves under the control of an integrated management program. Adults and larvae of O. v-nigrum (Mulsant) preying on premature Asian citrus psyllid were noticed in citrus groves throughout Florida [98].
A range of fungi species was reported to infect Asian citrus Psyllid, particularly under humid conditions [81], including entomopathogenic fungi, Isaria fumosorosea, Lecanicillium lecanii, Beauveria bassiana, Capnodium citri, Cladosporium sp. nr. Oxysporum, Metarhizium anisopliae, and Hirsutella citriformis that were used against HLB vectors as biopesticides [99, 100, 101]. Isaria fumosorosea is reported to have great potential to control different insect pests [102]. H. citriformis conidia with synnemata produced in vitro and in vivo were subjected to adult D. citri exhibits an increased mortality rate [100, 103]. In a 2-year field investigation in citrus groves in Florida, adult D. citri (ACP) was killed by H. citriformis following the rainy season [104]. In laboratory conditions, the fungal strains of Isaria fumosorosea (ESALQ-1296) and Beauveria bassiana (ESALQ-PL63) accounted for 77.8 and 78.4% of adult D. citri mortality, respectively, while in semifield conditions, adult D. citri mortality rate was as high as 83.5% with ESALQ-PL63 and 80.6% with ESALQ-1296. During 1 year, the monthly use of these two fungal strains in commercial citrus groves exhibited adult D. citri mortality ranging from 96.1% in December 2011 to 57.8% in October 2012. In addition, this study found that the mortality rate increased under high humidity conditions [99]. Isariajavanica and Acrostalagmus aphidum were also identified as biopesticides against D. citri in China [105]. The use of fungal species, such as Metarhizium anisopliae, Cordyceps bassiana, and Isaria fumosorosea, was shown to decrease larger populations of nymphs than adults of D. citri in the Persian lime groves [106].
5.1.2 RNA interference for vector control
RNA interference, a process in which a double-stranded RNA exerts a silencing effect on the complementary mRNA, has become a powerful tool in entomology. Advantages, such as ease of use, specific targeting, and lack of environmental persistence, make RNAi techniques highly attractive for crop protection against many insect pests [107]. The main challenges in using RNAi-based pest control methods are compelling target gene selection and reliable delivery of dsRNA. The over-expression of dsRNAs in transgenic plants has induced RNAi in targeted insects [108, 109]. The transgenic approach in citrus, however, is slow and difficult. Hajeri et al. [110] targeted D. citri endogenous Awd (abnormal wing development disc) gene for silencing by using a CTV-RNAi vector, resulting in impaired wings in D. citri that would potentially limit the ability to fly and successful transmission of CLas bacteria between citrus trees in the field. In addition, decreased Awd gene in nymphs resulted in malformed-wing phenotype in adults and increased adult mortality. Taning et al. [111] postulated that a small dose of dsRNA (dsAK, dsSOD) administered through in Planta system (iPS) bioassay was sufficient to trigger the RNAi mechanism, causing significant suppression of the targeted transcript and increased mortality in ACP.
5.1.3 Horticultural mineral oil for vector control
Petroleum-based horticultural mineral oils (HMO) are a vital constituent of integrated management programs for many pathogens and several phytophagous arthropods pathogens that affect the productivity of fruits, vegetables, and ornamentals in the commercial cultivation field as well as greenhouse conditions [112]. Since the 1980s, HMOs have been employed to control mites and scales in China [113]. HMO controls citrus leaf miner, citrus rust mite, citrus red mite, red scale, chaff scale, spiny whitefly, and Asian citrus Psyllid in citrus [114, 115]. By lowering the number of HMOs used in treatment to 0.25 ± 0.5% and maximizing the number of sprays during each season, a significant level of pest control was achieved without the threat of phytotoxicity. The combined treatment with oils and Isaria fumosorosea showed that the survival rate of adult psyllids was lower than that of oils used alone [116]. Kumar et al. [117] postulated that the combined treatment of entomopathogenic Isaria fumosoroseaand HMOs dramatically reduced D. citri populations, where the maximum mean survival for D. citri was 12.5 ± 0.7 days. Similarly, Tansey et al. [118] revealed that mixes of insecticide and HMO application considerably decreased the populations of nymph and adult D. citri in Valencia orange groves in Florida. Conversely, Qureshi et al. [119] disclosed that HMO alone did not control D. Citri populations because the mean suppression of nymph and adults for more than 3 weeks was only 36 and 50%, respectively.
5.2 Las bacterial control
5.2.1 Antibiotics
Antibiotics are crucial for controlling bacterial diseases in fruit-bearing trees, vegetables, and ornamentals. Although antibiotics can be detected on plant surfaces using delicate analytical chemistry techniques for up to a month after application, their ability to inhibit bacterial growth is lost within a week [120]. In-plant disease control, nearly 40 antibiotics were screened; only streptomycin and tetracycline were used extensively in fruit trees [121]. The only commercially applied treatment for HLB was tetracycline, which is bacteriostatic rather than bactericidal, in Reunion Island’s orchards [122, 123]. Tetracycline was the only approved antibiotic injection in trees injected directly into the trunks of HLB-affected citrus trees in China, Indonesia, India, Taiwan, and South Africa during the 1970s [36, 117, 124]. Although the symptoms of HLB were considerably decreased, this antibiotic trunk injection method was not in practice owing to its phytotoxicity and labor costs. The use of penicillin-carbendazim antibiotics in citrus trees showed significant control of HLB disease. The antibiotic disadvantage is a reduction in the fruit size owing to phytotoxicity and the residues of the antibiotics in citrus fruits [125]. The development of therapeutic compounds and bactericidal agents to control devastating HLB could provide an additional solution for an effective integrated disease management program. However, other than selective antibiotics, nonselective bactericide is recommended for general use in most crops, particularly citrus [126]. The combination treatment of streptomycin with penicillin efficiently eliminated or repressed the Las bacterium compared with the separate administration of either antibiotic [126]. The treatment of penicillin combined with streptomycin also significantly reduced the bacterial titer of Las in greenhouse citrus plants. Kasugamycin and Oxytetracycline combination therapy via trunk injection significantly reduced HLB bacterial titer in the field. However, the combination of kasugamycin and streptomycin was not effective against the bacterium of Las [127]. Penicillin with oxytetracycline combination therapy has been more effective in controlling citrus pathogens [128] but may require annual treatment [20]. Among the 31 tested antibiotics, some were effective at reducing and eliminating Las bacterial titers in inoculated rootstock and the treated scions of citrus plants, such as ampicillin, carbenicillin, penicillin, cefalexin, rifampicin, and sulfadimethoxine [20]. Oxytetracycline has therefore been suggested to be used more frequently in combination treatment [129, 130] with penicillin or kasugamycin against HLB to control the progression of bacterial resistance and maximize the antibiotic efficacy against HLB pathogenic bacteria [131]. The Environmental Protection Agency (EPA) of the USA allows citrus growers to spray streptomycin and oxytetracycline as routine treatments in the citrus field several times per year [132]. Oxytetracycline (1 g/L) was delivered to leaves of HLB-infected trees through the foliar application, and oxytetracycline was found in all leaves, although at reduced levels than in the directly applied leaves [132]. However, the phytotoxicity of tetracycline should be considered [20]. Antibiotics tested to combat HLB malady are tabulated inTable 1.
S.No
Antibiotics
Working concentration (mg/L)
Effectiveness
Phytotoxicity
1
Actidione
25
High
Highest
2
Validoxylamine A
100
Partly
Less
3
Zhongshengmycin
100
Partly
Less
4
Amikacin sulfate
100
None
NIL
5
Gentamicin sulfate
100
None
NIL
6
Hygromycin B
150
Partly
NIL
7
Kanamycin sulfate
100
Partly
None
8
Kasugamycin hydrochloride
100
None
NIL
9
Neomycin hydrate trisulfate
50
None
NIL
10
Spectinomycin dihydrochloride pentadrate
20
Partly
None
11
Streptomycin sulfate
100
None
NIL
12
Tobramycin
20
None
NIL
13
Ampicillin sodium
100
High
Less
14
Carbenicillin disodium
100
High
Less
15
Penicillin G potassium
100
High
Less
16
Cefalexin
100
High
Less
17
Vancomycin hydrochloride
40
None
NIL
18
Lincomycin hydrocloride
100
None
NIL
19
Cycloserine
50
Partly
NIL
20
Rifamycin sodium
50
Partly
Less
21
Rifampicin
50
High
Less
22
Rifaximin
50
Partly
Less
23
Colistinmethane sulfonate sodium
20
None
NIL
24
Polymixin B sulfate
300
None
NIL
25
Cinoxacin
300
None
NIL
26
Ciprofloxacin hydrochloride
300
Partly
NIL
27
Sulfadimethoxine sodium
100
Partly
Moderate
28
Sulfamethoxazole
100
Partly
Moderate
29
Sulfathiazole sodium
100
Partly
Moderate
30
Chloramphenicol
30
Partly
Less
31
Oxytetracycline hydrochloride
100
High
Highest
Table 1.
Antibiotics effectiveness against CLas bacterium and phytotoxicity.
5.2.2 Thermotherapy
Heat treatment or thermotherapy of planting material is a century-old disease control method that has proven effective against various pathogenic microorganisms. Thermotherapy, simple in principle, can eliminate the conserved pathogens depending on temperature/time regime and can cause mild injuries to the host during the treatment. Heat is mainly generated by water, vapor, or air [133]. The main advantage of thermotherapy treatment is that it is more environmentally friendly than harmful agrochemicals. Thermotherapy has proven to be an effective strategy against HLB that helps to enhance the vigor of citrus trees and promotes new root growth and development. The efficacy of thermotherapy against HLB pathogens depends on the temperature and citrus varieties [134]. Therapy could recuperate HLB-affected citrus plants by eliminating or suppressing Las bacterial titers at temperatures above 40°C [6, 134]. Candidatus Liberibacter asiaticus is a heat-tolerant phloem-limited bacteria that can withstand a temperature of about 35°C, while Candidatus Liberibacter americanus is heat-sensitive [135]. Thermotherapy could eliminate HLB pathogens from valuable horticultural trees associated with shoot tip grafting [136].
Lin opined on eliminating yellow shoot disease with water-saturated hot air treatment of graft wood 48–58°C with no loss of tissue viability [137]. In India, the thermotherapy of budwood at 47°C for 2 hours of diminished disease incidence, and more prolonged treatment eradicated the pathogen [138]. Heat treatment at temperatures around 38–40°C for 3 or 4 weeks killed HLB pathogens in young infected plants or citrus seedlings grafted with infected tissues [138, 139]. In South Africa, HLB-infected budwoods were treated with hot water baths at 51°C for 1 hour, 49°C for 2 hours, and 47°C for 4 hours, eliminating HLB pathogens with some loss of viability at higher temperatures [140]. In HLB-affected trees topped with polyethylene fiberglass sheets for 2 to 5 months, the number of diseased fruits decreased. However, this technique is not feasible for extensive use in citrus groves [27]. The HLB-affected citrus seedlings were continuously exposed to 40 to 42°C heat therapy for 7 to 10 days, significantly reducing titer or eliminating Las bacteria. This treatment can be helpful to combat HLB-affected plants in greenhouse and nursery settings [134]. Ehsani et al. [141] also postulated a decrease in HLB symptoms in groves of citrus trees after heat treatment. The combined thermo- and chemotherapy of sulfathiazole sodium or sulfadimethoxine sodium was more effective at 45°C than in thermotherapy alone, chemotherapy alone, or a combination of thermotherapy at 40°C and chemotherapy [142]. The temperature treatment at 45°C for 8 h per day for a week and a combination of ampicillin sodium, actidione, and validoxylamine A as a bark paint on grapefruits plant significantly reduced Las titer [143]. Two-year-old graft HLB-affected citrus reticulate treated with thermotherapy at 45°C and 48°C showed diminished HLB symptoms and Las titers 8 weeks after treatment in the greenhouse condition [144]. Commercial and residential citrus trees covered with portable plastic enclosures exposed to elevated temperatures through solarization showed vigorous growth in 3–6 weeks after treatment. Although commercial citrus trees showed Las after heat treatment, many trees generated extensive flushes and grew strongly for 2 to 3 years after therapy [145]. Inner bark heat treatment with 60°C–0.03 MPa-30s in 9-year-old citrus plants exhibited significantly reduced Las bacterial titer with vigorous plant growth from all treated HLB-affected trees [146]. Abdulridha et al. [147] reported that HLB-affected trees with canopy cover were treated with combined hot water and steam therapy at 55°C for 90 seconds. The temperature distribution inside the canopy cover was not uniform; the canopy temperatures were more significant than the trunk temperatures. The mobile thermotherapy treatment needs to be improved to increase the temperatures around the tree trunk to nearly the same temperature as a canopy. Vincent et al. [132] postulated that heat treatment from 43 to 54°C for no longer than 45 s showed adverse effects on citrus tree growth.
HLB is a systemic disease. Efficient elimination of Las bacteria from the entire citrus tree, including roots, is vital to managing the disease. The current thermotherapy challenge is that although adequately elevated temperatures can reach the above-ground areas of the plant, killing temperatures are unlikely to be attained at the roots where the temperature is mitigated by the soil [148]. Therefore, heat treatment is unlikely to reduce the populations of HLB pathogens in the roots, which then acts as a site for canopy reinfection during flushes. The efficacy of heat treatment in eliminating Las bacterial populations in underground roots must be enhanced to become a feasible part of integrated citrus HLB management [15]. To overcome this barrier, Hoffman et al. [134] suggest that heat treatment, coupled with chemotherapy in HLB-affected plants, can lead to a potential future strategy for controlling citrus HLB.
5.2.3 Plant defense activators to combat HLB
Trunk injection is an alternative target-precise technique for efficiently delivering plant protective chemicals in tree fruit crops. It harnesses the rapid transportation ability of the xylem that enables therapeutic compounds’ translocation and subsequent distribution into the canopy where plant protection is needed [149]. There has been limited research on the trunk injection of antibiotics and plant defense activators for better disease control. Several recent field studies have demonstrated the utility of trunk injection of bactericides and plant defense activators in disease management [150].
Treatments with β-aminobutyric acid (BABA), 2,1,3-benzothiadiazole (BTH), 2,6-dichloroisonicotinic acid (INA), ascorbic acid (AA), and the nonmetabolizable glucose analog 2-deoxy-D-glucose (2-DDG) plant defense inducers individually or in combination found effective in suppressing Las bacterial population in plants and sustaining fruit production to a certain extent. Treatment with BABA and BTH was the most effective in reducing the Las population in plant tissues compared with other plant defense inducers [151]. Hu and Wang proved that trunk injection of oxytetracycline in HLB-affected trees exhibited long-lasting suppression of Las populations. It also prevented the tree decline by promoting new growth without the disease [152]. Trunk injections of salicylic acid, potassium phosphate, acibenzolar-S-methyl, and oxalic acid in the HLB-affected tree significantly suppressed the Las titer and HLB disease progress [150].
Brassinosteroids (BRs) are a class of steroid hormones that regulate gene expression, growth, and developmental processes in response to biotic and abiotic stress [153]. The plant defense mechanism of brassinosteroids was mediated by leucine-rich repeat receptor kinase (LRR-RK) BAK1, which serves as a coreceptor for both microbe-associated molecular patterns (MAMPs) and steroid hormone [154], which binds to BRs and FLS2 eliciting microbe-induced immunity. BR treatment showed increasing disease resistance against many pathogens [6]. Canales et al. [155] postulated that applying epibrassinolide as a foliar spray in HLB-infected plants improved immunity against Candidatus Liberibacter asiaticus in greenhouse and field citrus plants. Candidatus Liberibacter asiaticus titer was markedly reduced in epibrassinolide-treated plants due to the enhanced defense gene expression in the citrus leaves. However, the molecular mechanism of BRs in plant responses under normal and environmentally challenging conditions has remained unclear [155].
5.3 Nanoemulsions to deliver chemicals against Las bacteria
HLB is caused by Las proteobacteria that reside in the phloem of infected citrus trees. It is, therefore, challenging to deliver effective compounds into the phloem through a foliar spray. The presence of wax, cutin, and pectin in plant cuticles prevents the effective bactericidal compounds from entering the phloem through a foliar spraying method. The use of chemical adjuvant enhanced the foliar uptake of agrochemicals [156, 157]. However, foliar spray treatment, including the combination of antibiotic PS and adjuvants in dimethyl sulfoxide and Silwet L-77, did not significantly impact the HLB-affected citrus trees [128]. Therefore, there is a need for candidate adjuvants, which can potentially increase the permeability of citrus cuticles to deliver antimicrobial compounds into citrus phloem.
Nanoemulsions or submicron emulsions are colloidal dispersion systems with average droplets size ranging from 50 to 1000 nm that has extensively studied for delivering chemical compounds. Nanoemulsions were pondered as thermodynamically and kinetically stable isotropic dispersions, composed of two immiscible liquids such as water and oil, stabilized by an interfacial film composed of an appropriate surfactant and co-surfactant to form a single-phase [158]. However, the approach efficacy relies on nanoemulsions droplet characteristics, such as low surface tension, tiny size, ample surface area, and low interface tension [159]. Our research group postulated that water in oil nanoemulsions containing ampicillin coupled with adjuvant Brij 35 was used as a foliar spray to enhance the permeability through the citrus cuticle into the phloem and more efficiently eliminated Las bacteria in HLB-affected citrus in planta [160]. Ampicillin showed the lowest phytotoxicity to citrus trees infected with Las bacteria [20]. However, the US Environmental Protection Agency (EPA) has not approved the commercial use of ampicillin in crops due to the development of resistant bacterial strains [160]. In another study, oil in water nanoemulsions was formulated using a spontaneous emulsification method, where five different antimicrobial compounds alone combined with Cremophor EL (viscous oil), acetone, and Span 80/Tween 80, which formed tiny droplets, were effectively applied to the bark for efficiently control HLB [161].
Silver nanoparticles (AgNPs) are one of the most investigated and used in agricultural science to enhance the yield and sustainable development of the crop. This has long been reported to have significant antibacterial, antifungal, antiviral, and pesticide effects. AgNPs are used as foliar sprays to prevent the development of rot, mold, fungi, and other plant pathogens [162]. Stephano-Hornedo et al. [18] evaluated the commercially available AgNPs to directly eradicate Candidatus Liberibacter asiaticus (CLas), responsible for HLB in the citrus field. The 93 HLB-infected citrus trees administered foliar and trunk injections of silver nanoparticles showed a remarkable reduction of 80–90% in bacterial titer by both methods than control. Compared with other effective treatments involving b-lactam antibiotics, the effectiveness of AgNPs is 3- to 60-fold higher when administered by foliar spray and 75- to 750-fold higher when injected via tree trunk. Thus, the silver nanoparticles could be a sustainable method for mitigating citrus HLB. However, AgNPs toxicity to a citrus tree and the environment needs to be warranted before its commercial use.
5.4 Transgenic approach to combat HLB
Globally, insect pests are responsible for significant crop losses through direct harm and transmission of plant diseases [163]. The best long-term alternative strategy for managing citrus HLB is to develop disease-resistant cultivars in commercial citrus production. Due to the lack of resistant cultivars, developing HLB-resistant plants by conventional citrus breeding is difficult. Resistance occurs in citrus relatives, such as kumquat, where its genetic background influences the quality and yield of the fruit [164]. In addition, conventional citrus breeding is labor- and time-consuming, and very costly as citrus species are polygenic, extremely heterozygous plants with a long juvenile phase. The genetic transformation approach is an essential strategy that would aid in incorporating disease-resistant genes into citrus cultivars to combat the HLB disease. The progression of citrus breeding through genetic transformation is still early, indicating a lack of molecular pathogenesis understanding of innate disease resistance in citrus [165].
Systemic acquired resistance (SAR), a natural plant defense response mechanism, has been well characterized in Arabidopsis thaliana. SAR entails signal molecule salicylic acid (SA) to activate defense mechanisms. In response to SA, the non-expression of pathogenesis-related gene 1 (NPR1) is translocated to the nucleus, where it triggers the expression of pathogenic related (PR) genes by interacting with TGA transcription factors, thereby provoking SAR [166, 167]. Arabidopsis mutants contain deficiencies in the NPR1 gene showing decreased PR gene expression induced by SA and SAR, leading to increased susceptibility to pathogens [167, 168]. Conversely, overexpression of the NPR1 gene in Arabidopsis increased the disease resistance to bacteria and oomycete pathogens. Interestingly, the over-expression of AtNPR1gene in most plant species does not provoke noticeable adverse effects on plant growth and development [169]. Thus, NPR1 is a target gene for the genetic transformation of nonspecific resistance in crop plants.
Dutt et al. [170] postulated that the overexpression of the AtNPR1 gene in Hamlin and Valencia orange cultivars resulted in trees with normal phenotypes, and exhibited increased resistance to HLB. Transgenic trees showed reduced disease severity, and a few lines remained disease-free even after 36 months of planting in a high-disease pressure field. The phloem-expressed NPR1 gene was equally effective in increasing disease resistance by triggering several indigenous gene expressions involving plant defense mechanisms of signaling pathways. In addition to triggering resistance to HLB, the observed SAR response could protect citrus trees from other major fungal and bacterial diseases, such as black spots and citrus canker [170].
6. Conclusions
HLB is one of the century-old diseases in the history of citrus pathology. The global spread of HLB disease causes economic loss in most citrus-producing countries. The causal agent of HLB, Candidatus Liberibacter, impedes understanding its pathogenic mechanism, fastidious nature, and unculturable in artificial conditions. Future research will focus on the isolation and pure culture of these proteobacteria. The rootstock and scion of some tolerant varieties have been noted and used by citrus growers in citriculture. These tolerant varieties have the potential to suppress the progression of HLB in Las-infected trees. The HLB management program recommends the intense psyllid control and removal of Las-infected trees in citrus groves. Citrus farmers focus on maintaining productivity in the HLB-affected trees by using plant defense activators, micronutrients, and fertilizers and paying more attention to water irrigation systems. Besides, thermotherapy is still an efficient methodology for eliminating and suppressing the causal agents in citrus scions and rootstock. Antibiotics alone or combined with other bactericides have also shown to be effective against citrus HLB. However, antibiotics need to evaluate their phytotoxicity before their commercial use. The combination of thermotherapy and antibiotics, plant defense activators, and thermotherapy provides controlled HLB management efficiency. The formation of nanoemulsion in water in oil (W/O) and/or oil in water (O/W) could offer a practical methodology for the targeted delivery of antimicrobial compounds to the phloem of citrus by foliar spraying method to control citrus HLB. In addition, transgenic orange cultivars over-expressing the AtNPR1 gene exhibited enhanced resistance to HLB. Transcriptome analysis between susceptible, tolerant, and resistant citrus varieties provides new insights into HLB tolerance by revealing defense-related genes, biological pathway signaling, hormones, transporters, carbohydrate metabolism, phloem-related genes, and secondary metabolism. In addition, some potential targets have also been identified, such as DMR6-like and NPR1-like genes for future HLB-tolerant citrus breeding [171]. Epibrassinolide as a foliar spray in HLB-affected plants improved the immunity against Candidatus Liberibacter asiaticus in the greenhouse and citrus field. However, further studies on the impact of eBL and nanoemulsion loaded with antibiotics in HLB-affected citrus plants are warranted to understand the complexity of citrus pathophysiology and fruit productivity. Researchers have investigated many control strategies to combat Candidatus Liberibacter species, but no effective management strategies have been developed. More studies are needed to investigate a sustainable and environmentally friendly strategy to control citrus HLB in the form of an antimicrobial agent in citrus groves. Meanwhile, biotechnological approaches such as transgenic, gene editing, and host-induced gene silencing may provide an unprecedented opportunity for long-term HLB management tools.
Based on the extensive prevention strategy experiments in the citriculture field by Chinese farmers, it has been shown that the control of HLB disease can be carried out in the three-pronged approach.
HLB-free seedlings. Selection of HLB-free citrus saplings, rootstocks, and scions. Furthermore, infected root stocks/scions might be cured through thermotherapy.
Removal of infected plants. Identification of HLB-affected plants by utilizing a suitable pathogen detection system and removing infected trees or infected sectors.
Suppress the psyllid. Control of psyllids to reduce the spread of HLB pathogens in the field and biological control of vectors might be desirable methods to control the vector populations rapidly and cost-effectively.
Nanotechnology-driven farming is still early, but it is an exciting and challenging field of research to be developed in the future, especially if the proper emphasis is placed on understanding the fundamental interactions between nanoscale materials and crop plants [172]. Future nanotechnology will enable the development of biosensors for early diagnosis of disease, new methods for suppression of disease pathogens in field and greenhouse conditions, and new molecular tools for understanding pathogenic mechanisms in pathogens and plants [173]. Nanotechnological investigations in phytopathology have increased dramatically over the last decade. Nanomaterials can be engineered as biosensors to diagnose plant diseases and as a means of delivery of genetic material, probes, and agrochemicals. Nanotechnology has been incorporated into disease management strategies, diagnostic tools, and molecular tools. Nanotechnologies could provide an alternative treatment to citrus farmers to be integrated into their existing HLB management programs in the citrus groves.
Acknowledgments
This work was funded by the Science and Technology Major Project of Guangxi (Gui Ke AA18118046).
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"citrus, Huanglongbing, Candidatus Liberibacter, control strategy, psyllid",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/82234.pdf",chapterXML:"https://mts.intechopen.com/source/xml/82234.xml",downloadPdfUrl:"/chapter/pdf-download/82234",previewPdfUrl:"/chapter/pdf-preview/82234",totalDownloads:31,totalViews:0,totalCrossrefCites:0,dateSubmitted:"April 8th 2022",dateReviewed:"April 28th 2022",datePrePublished:"June 15th 2022",datePublished:null,dateFinished:"June 15th 2022",readingETA:"0",abstract:"Huanglongbing (HLB) or greening is a devastating phloem-intruding bacterial disease that generates various symptoms in leaves and fruits, threatening the global citrus industry. Candidatus Liberibacter asiaticus, Candidatus Liberibacter africanus, and Candidatus Liberibacter americanus are the causative agents of HLB in citrus-producing regions around many countries, and these proteobacteria are being vectorized by Diaphorina citri and Triozaerytreae. The lack of HLB-resistant citrus cultivars, the rapid spread of disease, and the fastidious nature of HLB-proteobacteria have made it difficult to mitigate HLB in the citrus field. There are numerous reports on the control of HLB disease using thermotherapy, chemotherapy, plant defense activators, brassinosteroids, and nanoemulsions. However, there is no evidence of such applicability of the methods mentioned above to complete the elimination or suppression of the pathogen to control HLB disease. We aim to provide an overall picture of HLB disease, its distribution, causal organism, pathogenic mechanism, and current and future strategies for combat against citrus Huanglongbing disease. This review may prompt the researchers toward an integrated and environmentally sustainable methodology for the mitigation/elimination of HLB pathogens.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/82234",risUrl:"/chapter/ris/82234",signatures:"Palaniyandi Karuppaiya, Junyuan Huang and Muqing Zhang",book:{id:"11787",type:"book",title:"Current and Emerging Challenges in the Diseases of Trees",subtitle:null,fullTitle:"Current and Emerging Challenges in the Diseases of Trees",slug:null,publishedDate:null,bookSignature:"Dr. Cristiano Bellé",coverURL:"https://cdn.intechopen.com/books/images_new/11787.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80356-759-4",printIsbn:"978-1-80356-758-7",pdfIsbn:"978-1-80356-760-0",isAvailableForWebshopOrdering:!0,editors:[{id:"274523",title:"Dr.",name:"Cristiano",middleName:null,surname:"Bellé",slug:"cristiano-belle",fullName:"Cristiano Bellé"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Incidence, distribution, symptomology, and detection of citrus Huanglongbing",level:"1"},{id:"sec_2_2",title:"2.1 Incidence of Huanglongbing",level:"2"},{id:"sec_3_2",title:"2.2 Geographical distribution",level:"2"},{id:"sec_4_2",title:"2.3 Symptomology",level:"2"},{id:"sec_5_2",title:"2.4 Method of HLB detection",level:"2"},{id:"sec_7",title:"3. Causal agents of citrus Huanglongbing",level:"1"},{id:"sec_7_2",title:"3.1 In vitro culture of Candidatus Liberibacter species associated with HLB",level:"2"},{id:"sec_8_2",title:"3.2 The pathogenic mechanism of Candidatus Liberibacter",level:"2"},{id:"sec_8_3",title:"3.2.1 Liberibacter secretion system and effector protein",level:"3"},{id:"sec_9_3",title:"3.2.2 Lipopolysaccharides",level:"3"},{id:"sec_10_3",title:"3.2.3 Flagella",level:"3"},{id:"sec_11_3",title:"3.2.4 Prophages",level:"3"},{id:"sec_13_2",title:"3.3 Phloem dysfunction of HLB-affected citrus",level:"2"},{id:"sec_15",title:"4. Transmission of citrus HLB",level:"1"},{id:"sec_16",title:"5. Current strategies to combat citrus HLB",level:"1"},{id:"sec_16_2",title:"5.1 Vector control",level:"2"},{id:"sec_16_3",title:"5.1.1 Biocontrol of vector",level:"3"},{id:"sec_17_3",title:"5.1.2 RNA interference for vector control",level:"3"},{id:"sec_18_3",title:"5.1.3 Horticultural mineral oil for vector control",level:"3"},{id:"sec_20_2",title:"5.2 Las bacterial control",level:"2"},{id:"sec_20_3",title:"Table 1.",level:"3"},{id:"sec_21_3",title:"5.2.2 Thermotherapy",level:"3"},{id:"sec_22_3",title:"5.2.3 Plant defense activators to combat HLB",level:"3"},{id:"sec_24_2",title:"5.3 Nanoemulsions to deliver chemicals against Las bacteria",level:"2"},{id:"sec_25_2",title:"5.4 Transgenic approach to combat HLB",level:"2"},{id:"sec_27",title:"6. 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Nano in the future of crops. Nature Nanotechnology. 2019;14:507'},{id:"B173",body:'Elmer W, White JC. The future of nanotechnology in plant pathology. Annual Review of Phytopathology. 2018;56:111-133'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Palaniyandi Karuppaiya",address:null,affiliation:'
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State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi University, Nanning, China
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UK Research and Innovation (former Research Councils UK (RCUK) - including AHRC, BBSRC, ESRC, EPSRC, MRC, NERC, STFC.) Processing charges for books/book chapters can be covered through RCUK block grants which are allocated to most universities in the UK, which then handle the OA publication funding requests. It is at the discretion of the university whether it will approve the request.)
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He has published more than 50 papers in journals and 2 books.",institutionString:null,institution:{name:"Universitas Internasional Batam",country:{name:"Indonesia"}}},{id:"314576",title:"Dr.",name:"Ibai",middleName:null,surname:"Laña",slug:"ibai-lana",fullName:"Ibai Laña",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314576/images/system/314576.jpg",biography:"Dr. Ibai Laña works at TECNALIA as a data analyst. He received his Ph.D. in Artificial Intelligence from the University of the Basque Country (UPV/EHU), Spain, in 2018. He is currently a senior researcher at TECNALIA. His research interests fall within the intersection of intelligent transportation systems, machine learning, traffic data analysis, and data science. He has dealt with urban traffic forecasting problems, applying machine learning models and evolutionary algorithms. He has experience in origin-destination matrix estimation or point of interest and trajectory detection. Working with large volumes of data has given him a good command of big data processing tools and NoSQL databases. He has also been a visiting scholar at the Knowledge Engineering and Discovery Research Institute, Auckland University of Technology.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"314575",title:"Dr.",name:"Jesus",middleName:null,surname:"L. Lobo",slug:"jesus-l.-lobo",fullName:"Jesus L. Lobo",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/314575/images/system/314575.png",biography:"Dr. Jesús López is currently based in Bilbao (Spain) working at TECNALIA as Artificial Intelligence Research Scientist. In most cases, a project idea or a new research line needs to be investigated to see if it is good enough to take into production or to focus on it. That is exactly what he does, diving into Machine Learning algorithms and technologies to help TECNALIA to decide whether something is great in theory or will actually impact on the product or processes of its projects. So, he is expert at framing experiments, developing hypotheses, and proving whether they’re true or not, in order to investigate fundamental problems with a longer time horizon. He is also able to design and develop PoCs and system prototypes in simulation. He has participated in several national and internacional R&D projects.\n\nAs another relevant part of his everyday research work, he usually publishes his findings in reputed scientific refereed journals and international conferences, occasionally acting as reviewer and Programme Commitee member. Concretely, since 2018 he has published 9 JCR (8 Q1) journal papers, 9 conference papers (e.g. ECML PKDD 2021), and he has co-edited a book. He is also active in popular science writing data science stories for reputed blogs (KDNuggets, TowardsDataScience, Naukas). Besides, he has recently embarked on mentoring programmes as mentor, and has also worked as data science trainer.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"103779",title:"Prof.",name:"Yalcin",middleName:null,surname:"Isler",slug:"yalcin-isler",fullName:"Yalcin Isler",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRyQ8QAK/Profile_Picture_1628834958734",biography:"Yalcin Isler (1971 - Burdur / Turkey) received the B.Sc. degree in the Department of Electrical and Electronics Engineering from Anadolu University, Eskisehir, Turkey, in 1993, the M.Sc. degree from the Department of Electronics and Communication Engineering, Suleyman Demirel University, Isparta, Turkey, in 1996, the Ph.D. degree from the Department of Electrical and Electronics Engineering, Dokuz Eylul University, Izmir, Turkey, in 2009, and the Competence of Associate Professorship from the Turkish Interuniversity Council in 2019.\n\nHe was Lecturer at Burdur Vocational School in Suleyman Demirel University (1993-2000, Burdur / Turkey), Software Engineer (2000-2002, Izmir / Turkey), Research Assistant in Bulent Ecevit University (2002-2003, Zonguldak / Turkey), Research Assistant in Dokuz Eylul University (2003-2010, Izmir / Turkey), Assistant Professor at the Department of Electrical and Electronics Engineering in Bulent Ecevit University (2010-2012, Zonguldak / Turkey), Assistant Professor at the Department of Biomedical Engineering in Izmir Katip Celebi University (2012-2019, Izmir / Turkey). He is an Associate Professor at the Department of Biomedical Engineering at Izmir Katip Celebi University, Izmir / Turkey, since 2019. In addition to academics, he has also founded Islerya Medical and Information Technologies Company, Izmir / Turkey, since 2017.\n\nHis main research interests cover biomedical signal processing, pattern recognition, medical device design, programming, and embedded systems. He has many scientific papers and participated in several projects in these study fields. He was an IEEE Student Member (2009-2011) and IEEE Member (2011-2014) and has been IEEE Senior Member since 2014.",institutionString:null,institution:{name:"Izmir Kâtip Çelebi University",country:{name:"Turkey"}}},{id:"339677",title:"Dr.",name:"Mrinmoy",middleName:null,surname:"Roy",slug:"mrinmoy-roy",fullName:"Mrinmoy Roy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/339677/images/16768_n.jpg",biography:"An accomplished Sales & Marketing professional with 12 years of cross-functional experience in well-known organisations such as CIPLA, LUPIN, GLENMARK, ASTRAZENECA across different segment of Sales & Marketing, International Business, Institutional Business, Product Management, Strategic Marketing of HIV, Oncology, Derma, Respiratory, Anti-Diabetic, Nutraceutical & Stomatological Product Portfolio and Generic as well as Chronic Critical Care Portfolio. A First Class MBA in International Business & Strategic Marketing, B.Pharm, D.Pharm, Google Certified Digital Marketing Professional. Qualified PhD Candidate in Operations and Management with special focus on Artificial Intelligence and Machine Learning adoption, analysis and use in Healthcare, Hospital & Pharma Domain. Seasoned with diverse therapy area of Pharmaceutical Sales & Marketing ranging from generating revenue through generating prescriptions, launching new products, and making them big brands with continuous strategy execution at the Physician and Patients level. Moved from Sales to Marketing and Business Development for 3.5 years in South East Asian Market operating from Manila, Philippines. Came back to India and handled and developed Brands such as Gluconorm, Lupisulin, Supracal, Absolut Woman, Hemozink, Fabiflu (For COVID 19), and many more. In my previous assignment I used to develop and execute strategies on Sales & Marketing, Commercialization & Business Development for Institution and Corporate Hospital Business portfolio of Oncology Therapy Area for AstraZeneca Pharma India Ltd. Being a Research Scholar and Student of ‘Operations Research & Management: Artificial Intelligence’ I published several pioneer research papers and book chapters on the same in Internationally reputed journals and Books indexed in Scopus, Springer and Ei Compendex, Google Scholar etc. Currently, I am launching PGDM Pharmaceutical Management Program in IIHMR Bangalore and spearheading the course curriculum and structure of the same. I am interested in Collaboration for Healthcare Innovation, Pharma AI Innovation, Future trend in Marketing and Management with incubation on Healthcare, Healthcare IT startups, AI-ML Modelling and Healthcare Algorithm based training module development. I am also an affiliated member of the Institute of Management Consultant of India, looking forward to Healthcare, Healthcare IT and Innovation, Pharma and Hospital Management Consulting works.",institutionString:null,institution:{name:"Lovely Professional University",country:{name:"India"}}},{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. He has developed automation equipment for machine tools, spooling\nmachines, high-power ultrasound processes, and more.",institutionString:'"Politechnica" University Timişoara',institution:null},{id:"221364",title:"Dr.",name:"Eneko",middleName:null,surname:"Osaba",slug:"eneko-osaba",fullName:"Eneko Osaba",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/221364/images/system/221364.jpg",biography:"Dr. Eneko Osaba works at TECNALIA as a senior researcher. He obtained his Ph.D. in Artificial Intelligence in 2015. He has participated in more than twenty-five local and European research projects, and in the publication of more than 130 papers. He has performed several stays at universities in the United Kingdom, Italy, and Malta. Dr. Osaba has served as a program committee member in more than forty international conferences and participated in organizing activities in more than ten international conferences. He is a member of the editorial board of the International Journal of Artificial Intelligence, Data in Brief, and Journal of Advanced Transportation. He is also a guest editor for the Journal of Computational Science, Neurocomputing, Swarm, and Evolutionary Computation and IEEE ITS Magazine.",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"275829",title:"Dr.",name:"Esther",middleName:null,surname:"Villar-Rodriguez",slug:"esther-villar-rodriguez",fullName:"Esther Villar-Rodriguez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/275829/images/system/275829.jpg",biography:"Dr. Esther Villar obtained a Ph.D. in Information and Communication Technologies from the University of Alcalá, Spain, in 2015. She obtained a degree in Computer Science from the University of Deusto, Spain, in 2010, and an MSc in Computer Languages and Systems from the National University of Distance Education, Spain, in 2012. Her areas of interest and knowledge include natural language processing (NLP), detection of impersonation in social networks, semantic web, and machine learning. Dr. Esther Villar made several contributions at conferences and publishing in various journals in those fields. Currently, she is working within the OPTIMA (Optimization Modeling & Analytics) business of TECNALIA’s ICT Division as a data scientist in projects related to the prediction and optimization of management and industrial processes (resource planning, energy efficiency, etc).",institutionString:"TECNALIA Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:{name:"Tecnalia",country:{name:"Spain"}}},{id:"278948",title:"Dr.",name:"Carlos Pedro",middleName:null,surname:"Gonçalves",slug:"carlos-pedro-goncalves",fullName:"Carlos Pedro Gonçalves",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRcmyQAC/Profile_Picture_1564224512145",biography:'Carlos Pedro Gonçalves (PhD) is an Associate Professor at Lusophone University of Humanities and Technologies and a researcher on Complexity Sciences, Quantum Technologies, Artificial Intelligence, Strategic Studies, Studies in Intelligence and Security, FinTech and Financial Risk Modeling. He is also a progammer with programming experience in:\n\nA) Quantum Computing using Qiskit Python module and IBM Quantum Experience Platform, with software developed on the simulation of Quantum Artificial Neural Networks and Quantum Cybersecurity;\n\nB) Artificial Intelligence and Machine learning programming in Python;\n\nC) Artificial Intelligence, Multiagent Systems Modeling and System Dynamics Modeling in Netlogo, with models developed in the areas of Chaos Theory, Econophysics, Artificial Intelligence, Classical and Quantum Complex Systems Science, with the Econophysics models having been cited worldwide and incorporated in PhD programs by different Universities.\n\nReceived an Arctic Code Vault Contributor status by GitHub, due to having developed open source software preserved in the \\"Arctic Code Vault\\" for future generations (https://archiveprogram.github.com/arctic-vault/), with the Strategy Analyzer A.I. module for decision making support (based on his PhD thesis, used in his Classes on Decision Making and in Strategic Intelligence Consulting Activities) and QNeural Python Quantum Neural Network simulator also preserved in the \\"Arctic Code Vault\\", for access to these software modules see: https://github.com/cpgoncalves. He is also a peer reviewer with outsanding review status from Elsevier journals, including Physica A, Neurocomputing and Engineering Applications of Artificial Intelligence. Science CV available at: https://www.cienciavitae.pt//pt/8E1C-A8B3-78C5 and ORCID: https://orcid.org/0000-0002-0298-3974',institutionString:"University of Lisbon",institution:{name:"Universidade Lusófona",country:{name:"Portugal"}}},{id:"310576",title:"Prof.",name:"Erick Giovani",middleName:null,surname:"Sperandio Nascimento",slug:"erick-giovani-sperandio-nascimento",fullName:"Erick Giovani Sperandio Nascimento",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0033Y00002pDKxDQAW/ProfilePicture%202022-06-20%2019%3A57%3A24.788",biography:"Prof. Erick Sperandio is the Lead Researcher and professor of Artificial Intelligence (AI) at SENAI CIMATEC, Bahia, Brazil, also working with Computational Modeling (CM) and HPC. He holds a PhD in Environmental Engineering in the area of Atmospheric Computational Modeling, a Master in Informatics in the field of Computational Intelligence and Graduated in Computer Science from UFES. He currently coordinates, leads and participates in R&D projects in the areas of AI, computational modeling and supercomputing applied to different areas such as Oil and Gas, Health, Advanced Manufacturing, Renewable Energies and Atmospheric Sciences, advising undergraduate, master's and doctoral students. He is the Lead Researcher at SENAI CIMATEC's Reference Center on Artificial Intelligence. In addition, he is a Certified Instructor and University Ambassador of the NVIDIA Deep Learning Institute (DLI) in the areas of Deep Learning, Computer Vision, Natural Language Processing and Recommender Systems, and Principal Investigator of the NVIDIA/CIMATEC AI Joint Lab, the first in Latin America within the NVIDIA AI Technology Center (NVAITC) worldwide program. He also works as a researcher at the Supercomputing Center for Industrial Innovation (CS2i) and at the SENAI Institute of Innovation for Automation (ISI Automação), both from SENAI CIMATEC. He is a member and vice-coordinator of the Basic Board of Scientific-Technological Advice and Evaluation, in the area of Innovation, of the Foundation for Research Support of the State of Bahia (FAPESB). He serves as Technology Transfer Coordinator and one of the Principal Investigators at the National Applied Research Center in Artificial Intelligence (CPA-IA) of SENAI CIMATEC, focusing on Industry, being one of the six CPA-IA in Brazil approved by MCTI / FAPESP / CGI.br. He also participates as one of the representatives of Brazil in the BRICS Innovation Collaboration Working Group on HPC, ICT and AI. He is the coordinator of the Work Group of the Axis 5 - Workforce and Training - of the Brazilian Strategy for Artificial Intelligence (EBIA), and member of the MCTI/EMBRAPII AI Innovation Network Training Committee. He is the coordinator, by SENAI CIMATEC, of the Artificial Intelligence Reference Network of the State of Bahia (REDE BAH.IA). He leads the working group of experts representing Brazil in the Global Partnership on Artificial Intelligence (GPAI), on the theme \"AI and the Pandemic Response\".",institutionString:null,institution:null},{id:"241400",title:"Prof.",name:"Mohammed",middleName:null,surname:"Bsiss",slug:"mohammed-bsiss",fullName:"Mohammed Bsiss",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/241400/images/8062_n.jpg",biography:null,institutionString:null,institution:null},{id:"276128",title:"Dr.",name:"Hira",middleName:null,surname:"Fatima",slug:"hira-fatima",fullName:"Hira Fatima",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/276128/images/14420_n.jpg",biography:"Dr. Hira Fatima\nAssistant Professor\nDepartment of Mathematics\nInstitute of Applied Science\nMangalayatan University, Aligarh\nMobile: no : 8532041179\nhirafatima2014@gmal.com\n\nDr. Hira Fatima has received his Ph.D. degree in pure Mathematics from Aligarh Muslim University, Aligarh India. Currently working as an Assistant Professor in the Department of Mathematics, Institute of Applied Science, Mangalayatan University, Aligarh. She taught so many courses of Mathematics of UG and PG level. Her research Area of Expertise is Functional Analysis & Sequence Spaces. She has been working on Ideal Convergence of double sequence. She has published 17 research papers in National and International Journals including Cogent Mathematics, Filomat, Journal of Intelligent and Fuzzy Systems, Advances in Difference Equations, Journal of Mathematical Analysis, Journal of Mathematical & Computer Science etc. She has also reviewed few research papers for the and international journals. She is a member of Indian Mathematical Society.",institutionString:null,institution:null},{id:"417317",title:"Mrs.",name:"Chiedza",middleName:null,surname:"Elvina Mashiri",slug:"chiedza-elvina-mashiri",fullName:"Chiedza Elvina Mashiri",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"352140",title:"Dr.",name:"Edina",middleName:null,surname:"Chandiwana",slug:"edina-chandiwana",fullName:"Edina Chandiwana",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"342259",title:"B.Sc.",name:"Leonard",middleName:null,surname:"Mushunje",slug:"leonard-mushunje",fullName:"Leonard Mushunje",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"347042",title:"Mr.",name:"Maxwell",middleName:null,surname:"Mashasha",slug:"maxwell-mashasha",fullName:"Maxwell Mashasha",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Midlands State University",country:{name:"Zimbabwe"}}},{id:"2941",title:"Dr.",name:"Alberto J.",middleName:"Jorge",surname:"Rosales-Silva",slug:"alberto-j.-rosales-silva",fullName:"Alberto J. Rosales-Silva",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"437913",title:"Dr.",name:"Guillermo",middleName:null,surname:"Urriolagoitia-Sosa",slug:"guillermo-urriolagoitia-sosa",fullName:"Guillermo Urriolagoitia-Sosa",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"435126",title:"Prof.",name:"Joaquim",middleName:null,surname:"José de Castro Ferreira",slug:"joaquim-jose-de-castro-ferreira",fullName:"Joaquim José de Castro Ferreira",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Aveiro",country:{name:"Portugal"}}},{id:"437899",title:"MSc.",name:"Miguel Angel",middleName:null,surname:"Ángel Castillo-Martínez",slug:"miguel-angel-angel-castillo-martinez",fullName:"Miguel Angel Ángel Castillo-Martínez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"289955",title:"Dr.",name:"Raja",middleName:null,surname:"Kishor Duggirala",slug:"raja-kishor-duggirala",fullName:"Raja Kishor Duggirala",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jawaharlal Nehru Technological University, Hyderabad",country:{name:"India"}}}]}},subseries:{item:{id:"27",type:"subseries",title:"Multi-Agent Systems",keywords:"Collaborative Intelligence, Learning, Distributed Control System, Swarm Robotics, Decision Science, Software Engineering",scope:"Multi-agent systems are recognised as a state of the art field in Artificial Intelligence studies, which is popular due to the usefulness in facilitation capabilities to handle real-world problem-solving in a distributed fashion. The area covers many techniques that offer solutions to emerging problems in robotics and enterprise-level software systems. Collaborative intelligence is highly and effectively achieved with multi-agent systems. Areas of application include swarms of robots, flocks of UAVs, collaborative software management. Given the level of technological enhancements, the popularity of machine learning in use has opened a new chapter in multi-agent studies alongside the practical challenges and long-lasting collaboration issues in the field. It has increased the urgency and the need for further studies in this field. We welcome chapters presenting research on the many applications of multi-agent studies including, but not limited to, the following key areas: machine learning for multi-agent systems; modeling swarms robots and flocks of UAVs with multi-agent systems; decision science and multi-agent systems; software engineering for and with multi-agent systems; tools and technologies of multi-agent systems.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",hasOnlineFirst:!0,hasPublishedBooks:!1,annualVolume:11423,editor:{id:"148497",title:"Dr.",name:"Mehmet",middleName:"Emin",surname:"Aydin",slug:"mehmet-aydin",fullName:"Mehmet Aydin",profilePictureURL:"https://mts.intechopen.com/storage/users/148497/images/system/148497.jpg",biography:"Dr. Mehmet Emin Aydin is a Senior Lecturer with the Department of Computer Science and Creative Technology, the University of the West of England, Bristol, UK. His research interests include swarm intelligence, parallel and distributed metaheuristics, machine learning, intelligent agents and multi-agent systems, resource planning, scheduling and optimization, combinatorial optimization. Dr. Aydin is currently a Fellow of Higher Education Academy, UK, a member of EPSRC College, a senior member of IEEE and a senior member of ACM. In addition to being a member of advisory committees of many international conferences, he is an Editorial Board Member of various peer-reviewed international journals. 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\r\n\tThe era of antibiotics led us to the illusion that the problem of bacterial infection is over. However, bacterial flexibility and adaptation mechanisms allow them to survive and grow in extreme conditions. The best example is the formation of a sophisticated society of bacteria defined as a biofilm. Understanding the mechanism of bacterial biofilm formation has changed our perception of the development of bacterial infection but successfully eradicating biofilm remains a challenge. Considering the above, it is not surprising that bacteria remain a major public health threat despite the development of many groups of antibiotics. Additionally, increasing prevalence of acquired antibiotic resistance forces us to realize that we are far from controlling the development of bacterial infections. On the other hand, many infections are endogenous and result from an unbalanced relationship between the host and the microorganism. The increasing use of immunosuppressants, such as chemotherapy or organ transplantation, increases the incidence of patients highly susceptible to bacterial infections in the population.
\r\n
\r\n\tThis topic will focus on the current challenges and advantages in the diagnosis and treatment of bacterial infections. We will discuss the host-microbiota relationship, the treatment of chronic infections due to biofilm formation, and the development of new diagnostic tools to rapidly distinguish between colonization and probable infection.
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Special attention should be given to endemic fungal infections, identification of important clinical fungal infections advanced in yeasts, filamentous fungal infections, skin mycobiome and fungal genomes, and immunity to fungal infections.\r\nIn addition, endemic fungal diseases or uncommon fungal infections caused by Mucor irregularis, dermatophytosis, Malassezia, cryptococcosis, chromoblastomycosis, coccidiosis, blastomycosis, histoplasmosis, sporotrichosis, and other fungi, should be monitored. \r\nThis topic includes the research progress on the etiology and pathogenesis of fungal infections, new methods of isolation and identification, rapid detection, drug sensitivity testing, new antifungal drugs, schemes and case series reports. 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Many parasitic diseases are classified as neglected tropical diseases because they have received minimal funding over recent years and, in many cases, are under-reported despite the critical role they play in morbidity and mortality among human and animal hosts. The current topic, Parasitic Infectious Diseases, in the Infectious Diseases Series aims to publish studies on the systematics, epidemiology, molecular biology, genomics, pathogenesis, genetics, and clinical significance of parasitic diseases from blood borne to intestinal parasites as well as zoonotic parasites. We hope to cover all aspects of parasitic diseases to provide current and relevant research data on these very important diseases. In the current atmosphere of the Coronavirus pandemic, communities around the world, particularly those in different underdeveloped areas, are faced with the growing challenges of the high burden of parasitic diseases. At the same time, they are faced with the Covid-19 pandemic leading to what some authors have called potential syndemics that might worsen the outcome of such infections. Therefore, it is important to conduct studies that examine parasitic infections in the context of the coronavirus pandemic for the benefit of all communities to help foster more informed decisions for the betterment of human and animal health.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",keywords:"Blood Borne Parasites, Intestinal Parasites, Protozoa, Helminths, Arthropods, Water Born Parasites, Epidemiology, Molecular Biology, Systematics, Genomics, Proteomics, Ecology"},{id:"6",title:"Viral Infectious Diseases",scope:"The Viral Infectious Diseases Book Series aims to provide a comprehensive overview of recent research trends and discoveries in various viral infectious diseases emerging around the globe. The emergence of any viral disease is hard to anticipate, which often contributes to death. A viral disease can be defined as an infectious disease that has recently appeared within a population or exists in nature with the rapid expansion of incident or geographic range. 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\r\n\tThe era of antibiotics led us to the illusion that the problem of bacterial infection is over. However, bacterial flexibility and adaptation mechanisms allow them to survive and grow in extreme conditions. The best example is the formation of a sophisticated society of bacteria defined as a biofilm. Understanding the mechanism of bacterial biofilm formation has changed our perception of the development of bacterial infection but successfully eradicating biofilm remains a challenge. Considering the above, it is not surprising that bacteria remain a major public health threat despite the development of many groups of antibiotics. Additionally, increasing prevalence of acquired antibiotic resistance forces us to realize that we are far from controlling the development of bacterial infections. On the other hand, many infections are endogenous and result from an unbalanced relationship between the host and the microorganism. The increasing use of immunosuppressants, such as chemotherapy or organ transplantation, increases the incidence of patients highly susceptible to bacterial infections in the population.
\r\n
\r\n\tThis topic will focus on the current challenges and advantages in the diagnosis and treatment of bacterial infections. We will discuss the host-microbiota relationship, the treatment of chronic infections due to biofilm formation, and the development of new diagnostic tools to rapidly distinguish between colonization and probable infection.
",annualVolume:11399,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/3.jpg",editor:{id:"205604",title:"Dr.",name:"Tomas",middleName:null,surname:"Jarzembowski",fullName:"Tomas Jarzembowski",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKriQAG/Profile_Picture_2022-06-16T11:01:31.jpg",institutionString:"Medical University of Gdańsk, Poland",institution:null},editorTwo:{id:"484980",title:"Dr.",name:"Katarzyna",middleName:null,surname:"Garbacz",fullName:"Katarzyna Garbacz",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003St8TAQAZ/Profile_Picture_2022-07-07T09:45:16.jpg",institutionString:"Medical University of Gdańsk, Poland",institution:null},editorThree:null,editorialBoard:[{id:"190041",title:"Dr.",name:"Jose",middleName:null,surname:"Gutierrez Fernandez",fullName:"Jose Gutierrez Fernandez",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"University of Granada",institutionURL:null,country:{name:"Spain"}}},{id:"156556",title:"Prof.",name:"Maria Teresa",middleName:null,surname:"Mascellino",fullName:"Maria Teresa Mascellino",profilePictureURL:"https://mts.intechopen.com/storage/users/156556/images/system/156556.jpg",institutionString:"Sapienza University",institution:{name:"Sapienza University of Rome",institutionURL:null,country:{name:"Italy"}}},{id:"164933",title:"Prof.",name:"Mónica Alexandra",middleName:null,surname:"Sousa Oleastro",fullName:"Mónica Alexandra Sousa Oleastro",profilePictureURL:"https://mts.intechopen.com/storage/users/164933/images/system/164933.jpeg",institutionString:"National Institute of Health Dr Ricardo Jorge",institution:{name:"National Institute of Health Dr. Ricardo Jorge",institutionURL:null,country:{name:"Portugal"}}}]},{id:"4",title:"Fungal Infectious Diseases",keywords:"Emerging Fungal Pathogens, Invasive Infections, Epidemiology, Cell Membrane, Fungal Virulence, Diagnosis, Treatment",scope:"Fungi are ubiquitous and there are almost no non-pathogenic fungi. Fungal infectious illness prevalence and prognosis are determined by the exposure between fungi and host, host immunological state, fungal virulence, and early and accurate diagnosis and treatment. \r\nPatients with both congenital and acquired immunodeficiency are more likely to be infected with opportunistic mycosis. Fungal infectious disease outbreaks are common during the post- disaster rebuilding era, which is characterised by high population density, migration, and poor health and medical conditions.\r\nSystemic or local fungal infection is mainly associated with the fungi directly inhaled or inoculated in the environment during the disaster. The most common fungal infection pathways are human to human (anthropophilic), animal to human (zoophilic), and environment to human (soilophile). Diseases are common as a result of widespread exposure to pathogenic fungus dispersed into the environment. \r\nFungi that are both common and emerging are intertwined. In Southeast Asia, for example, Talaromyces marneffei is an important pathogenic thermally dimorphic fungus that causes systemic mycosis. Widespread fungal infections with complicated and variable clinical manifestations, such as Candida auris infection resistant to several antifungal medicines, Covid-19 associated with Trichoderma, and terbinafine resistant dermatophytosis in India, are among the most serious disorders. \r\nInappropriate local or systemic use of glucocorticoids, as well as their immunosuppressive effects, may lead to changes in fungal infection spectrum and clinical characteristics. Hematogenous candidiasis is a worrisome issue that affects people all over the world, particularly ICU patients. CARD9 deficiency and fungal infection have been major issues in recent years. Invasive aspergillosis is associated with a significant death rate. Special attention should be given to endemic fungal infections, identification of important clinical fungal infections advanced in yeasts, filamentous fungal infections, skin mycobiome and fungal genomes, and immunity to fungal infections.\r\nIn addition, endemic fungal diseases or uncommon fungal infections caused by Mucor irregularis, dermatophytosis, Malassezia, cryptococcosis, chromoblastomycosis, coccidiosis, blastomycosis, histoplasmosis, sporotrichosis, and other fungi, should be monitored. \r\nThis topic includes the research progress on the etiology and pathogenesis of fungal infections, new methods of isolation and identification, rapid detection, drug sensitivity testing, new antifungal drugs, schemes and case series reports. It will provide significant opportunities and support for scientists, clinical doctors, mycologists, antifungal drug researchers, public health practitioners, and epidemiologists from all over the world to share new research, ideas and solutions to promote the development and progress of medical mycology.",annualVolume:11400,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",editor:{id:"174134",title:"Dr.",name:"Yuping",middleName:null,surname:"Ran",fullName:"Yuping Ran",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9d6QAC/Profile_Picture_1630330675373",institutionString:null,institution:{name:"Sichuan University",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"302145",title:"Dr.",name:"Felix",middleName:null,surname:"Bongomin",fullName:"Felix Bongomin",profilePictureURL:"https://mts.intechopen.com/storage/users/302145/images/system/302145.jpg",institutionString:null,institution:{name:"Gulu University",institutionURL:null,country:{name:"Uganda"}}},{id:"45803",title:"Ph.D.",name:"Payam",middleName:null,surname:"Behzadi",fullName:"Payam Behzadi",profilePictureURL:"https://mts.intechopen.com/storage/users/45803/images/system/45803.jpg",institutionString:"Islamic Azad University, Tehran",institution:{name:"Islamic Azad University, Tehran",institutionURL:null,country:{name:"Iran"}}}]},{id:"5",title:"Parasitic Infectious Diseases",keywords:"Blood Borne Parasites, Intestinal Parasites, Protozoa, Helminths, Arthropods, Water Born Parasites, Epidemiology, Molecular Biology, Systematics, Genomics, Proteomics, Ecology",scope:"Parasitic diseases have evolved alongside their human hosts. In many cases, these diseases have adapted so well that they have developed efficient resilience methods in the human host and can live in the host for years. Others, particularly some blood parasites, can cause very acute diseases and are responsible for millions of deaths yearly. Many parasitic diseases are classified as neglected tropical diseases because they have received minimal funding over recent years and, in many cases, are under-reported despite the critical role they play in morbidity and mortality among human and animal hosts. The current topic, Parasitic Infectious Diseases, in the Infectious Diseases Series aims to publish studies on the systematics, epidemiology, molecular biology, genomics, pathogenesis, genetics, and clinical significance of parasitic diseases from blood borne to intestinal parasites as well as zoonotic parasites. We hope to cover all aspects of parasitic diseases to provide current and relevant research data on these very important diseases. In the current atmosphere of the Coronavirus pandemic, communities around the world, particularly those in different underdeveloped areas, are faced with the growing challenges of the high burden of parasitic diseases. At the same time, they are faced with the Covid-19 pandemic leading to what some authors have called potential syndemics that might worsen the outcome of such infections. Therefore, it is important to conduct studies that examine parasitic infections in the context of the coronavirus pandemic for the benefit of all communities to help foster more informed decisions for the betterment of human and animal health.",annualVolume:11401,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",editor:{id:"67907",title:"Dr.",name:"Amidou",middleName:null,surname:"Samie",fullName:"Amidou Samie",profilePictureURL:"https://mts.intechopen.com/storage/users/67907/images/system/67907.jpg",institutionString:null,institution:{name:"University of Venda",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"188881",title:"Dr.",name:"Fernando José",middleName:null,surname:"Andrade-Narváez",fullName:"Fernando José Andrade-Narváez",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRIV7QAO/Profile_Picture_1628834308121",institutionString:null,institution:{name:"Autonomous University of Yucatán",institutionURL:null,country:{name:"Mexico"}}},{id:"269120",title:"Dr.",name:"Rajeev",middleName:"K.",surname:"Tyagi",fullName:"Rajeev Tyagi",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRaBqQAK/Profile_Picture_1644331884726",institutionString:"CSIR - Institute of Microbial Technology, India",institution:null},{id:"336849",title:"Prof.",name:"Ricardo",middleName:null,surname:"Izurieta",fullName:"Ricardo Izurieta",profilePictureURL:"https://mts.intechopen.com/storage/users/293169/images/system/293169.png",institutionString:null,institution:{name:"University of South Florida",institutionURL:null,country:{name:"United States of America"}}}]},{id:"6",title:"Viral Infectious Diseases",keywords:"Novel Viruses, Virus Transmission, Virus Evolution, Molecular Virology, Control and Prevention, Virus-host Interaction",scope:"The Viral Infectious Diseases Book Series aims to provide a comprehensive overview of recent research trends and discoveries in various viral infectious diseases emerging around the globe. The emergence of any viral disease is hard to anticipate, which often contributes to death. A viral disease can be defined as an infectious disease that has recently appeared within a population or exists in nature with the rapid expansion of incident or geographic range. This series will focus on various crucial factors related to emerging viral infectious diseases, including epidemiology, pathogenesis, host immune response, clinical manifestations, diagnosis, treatment, and clinical recommendations for managing viral infectious diseases, highlighting the recent issues with future directions for effective therapeutic strategies.",annualVolume:11402,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",editor:{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",fullName:"Emmanuel Drouet",profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",institutionString:null,institution:{name:"Grenoble Alpes University",institutionURL:null,country:{name:"France"}}},{id:"188219",title:"Prof.",name:"Imran",middleName:null,surname:"Shahid",fullName:"Imran Shahid",profilePictureURL:"https://mts.intechopen.com/storage/users/188219/images/system/188219.jpeg",institutionString:null,institution:{name:"Umm al-Qura University",institutionURL:null,country:{name:"Saudi Arabia"}}},{id:"214235",title:"Dr.",name:"Lynn",middleName:"S.",surname:"Zijenah",fullName:"Lynn Zijenah",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSEJGQA4/Profile_Picture_1636699126852",institutionString:null,institution:{name:"University of Zimbabwe",institutionURL:null,country:{name:"Zimbabwe"}}},{id:"178641",title:"Dr.",name:"Samuel Ikwaras",middleName:null,surname:"Okware",fullName:"Samuel Ikwaras Okware",profilePictureURL:"https://mts.intechopen.com/storage/users/178641/images/system/178641.jpg",institutionString:null,institution:{name:"Uganda Christian University",institutionURL:null,country:{name:"Uganda"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/110381",hash:"",query:{},params:{id:"110381"},fullPath:"/profiles/110381",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()