Abstract
Xanthomonas citri subsp. citri (Xcc) is the etiological agent of citrus canker, a disease that affects almost all types of citrus crops. Production of Xcc virulence factors is controlled by a gene cluster rpf, which encodes elements of a cell-cell communication system called quorum sensing (QS). Perturbation of cell-cell signaling systems either by signal degradation or by overproduction significantly reduces symptoms and thereby the severity of the disease. Pathogenicity assays in Citrus sinensis showed that some bacterial species natural inhabitants of citrus phyllosphera have the strong ability to disturb QS system mediated by diffusible signal factor (DSF) molecule in Xcc and to reduce disease severity. The lessening of symptoms was associated with alteration in bacterial attachment and biofilm formation. These factors are known to contribute to Xcc virulence in the early stages of disease. The aim of this chapter is to review QS system in Xcc, the virulence factors affected by QS disturbing, as well as the main secretion systems that participate actively in virulence and its effect on the symptomatology of citrus canker.
Keywords
- Xanthomonas citri
- DSF
- quorum quenching
- biofilm
- adhesin
1. Introduction
Of the entire bacterial population that comprise the plant microbiome, both phyllosphere and rhizosphere, the vast majority live as saprophyte on the plant surfaces and a few of them get internalized into the plant tissues, without causing any damage to their host; only about 100 bacterial species has became pathogenic to their host. Pathogenicity of microorganisms is due to the expression of virulence factors, which could be attributed to their genetic, biochemical, or structural traits in the attempt to produce host infection. Quorum sensing (QS) is a cell-cell communication system, which leads to the regulation of specific genes, which in bacteria control essential biological functions as bioluminescence, antibiotic production, virulence, motility, and biofilm formation. In the bacterium
2. X. citri subsp. citri virulence factors
The genus
The bacterium
2.1. Adhesins
A fundamental step in the bacterial colonization of host is its ability to attach to the surface of host cells. Bacterial surface structures anchored in its outer membrane that enables adhesion are termed adhesins, which are mostly of polysaccharidic nature (lipopolysaccharides (LPS) and exopolysaccharides) but may also be of proteinaceous nature (type IV pili, chaperone/usher pili, two-partner secretion) [6].
2.1.1. Lipopolysaccharide and exopolysaccharide
The lipopolysaccharides (LPS) play a role in adhesion, but it is difficult to determine whether it affects directly or indirectly the bacterial adhesion [7]. LPS is a crucial constituent of the outer membrane in Gram-negative bacteria and plays multiple roles in plant-microbe interactions [8]. LPS acts as a barrier for protecting bacteria from adverse environmental factors such as antibacterial compounds produced by the host cell, besides triggering or enhancing plant-defenses responses, because it acts as pathogen-associated molecular pattern (PAMP) identified in a widespread variety of phytopathogenic bacteria [9]. A recent study by Casabuono et al. [10] identified the structure of LPS in Xcc as a penta- or tetra-acylated diglucosamine backbone attached to either two pyrophosphorylethanolamine (PP-EtNH2) groups or to one PP-EtNH2 group and one phosphorylethanolamine group. The core region is composed by a branched oligosaccharide and two phosphate groups, whereas the O-antigen consists of a rhamnose homo-oligosaccharide. Xcc mutants of
The exopolysaccharide (EPS) in
2.1.2. Proteic attachment structures
Pili (fimbriae) are filamentous appendices linked to cell surface; it has been categorized by their potential to induce hemagglutination, their anchoring site in bacteria (i.e., polar or omnidirectional) and their size. Several types of pili in
Homopolymeric ensemble of the pilin proteins termed PilA and PilE is the main constituent of
Genes that encode for type I pili or CU pili (chaperone/usher) were first demonstrated in
2.2. Pigment xanthomonadin
Members of the group of
2.3. Virulence-related protein secretion systems and their effectors
Bacteria belonging to
2.3.1. T2 secretion system (T2SS)
The T2SS was initially discovered in
2.3.2. T3 Secretion system (T3SS)
Pathogenic bacteria employ the T3SS secretion system termed “needle,” in order to provide virulence factors (effectors) directly into host cells and consequently influence cell host activities [20]. Initially, the T3SS has been identified and studied in pathogenic animal bacteria, such as
In the Xcc genome, 24 known and putative effectors have been identified [36]. One of the principal effectors carried by the T3SS in Xcc belongs to the family AvrBs3/PthA. These effectors contain functional domains characteristic of eukaryotic transcriptional activator and are thus named TALE (Transcription Activators Like Effector) [37]. Particularly, TALE contains a central repeat domain that recognizes the host DNA in a highly specific fashion. Each repeating unit contains 34 amino acids, with 12 and 13 hyper-variable amino acids termed VRD (Variable Repeat Di-residue). Thus, the composition and arrangement of different VRDs provide TALEs with tremendous capacity to recognize DNA host, and binding occurs with a high degree of specificity to a particular region at the promoter of target gene known as EBE (Effector Binding Element). Bioinformatics and experimental approach sophisticatedly demonstrated that each VRD type acts as a code recognizing a specific nucleotide [38]. Xcc contains four genes (
2.3.3. T4 secretion system (T4SS)
The translocator apparatus designated as type IV secretion system (T4SS) is an important virulence factor in several animals and plants bacterial pathogens, T4SS involving the secretion of proteins or DNA into the host cells [41]. The T4SS apparatus extends from the bacterial inner membrane through the periplasm; it ends at the outer membrane into a pilus-like structure, which protrudes from the surface of the bacterial cell. Several studies made on the
3. Citrus canker, life cycle, symptoms, and types of diseases
One of the most important citrus diseases is citrus canker, affecting almost all types of citrus crops. The disease causes extensive damage to the cultivars and severity of infection varies with different bacterial species and the predominant weather conditions. The geographical origin of citrus canker is a matter of controversy. Lee et al. [45] reported that citrus canker may have emerged in southern China. However, several authors believe that the disease had its origin in particular regions of India and Java [46]. These reports suggest, therefore, that the origin of the disease has occurred in tropical areas of Asia, where it is assumed that citrus species have originated and been distributed to other areas through vegetative propagation material. Currently, citrus canker occurs in over 30 countries in Asia, Indian and Pacific Ocean islands, South America, and Southeast of USA [47]. Copper-based products are routinely used as a standard control measure for citrus canker.
The invasion and colonization of the host occur through natural openings of the leaves (the stomata) and wounds in the plant tissues. The pathogen multiplies within the intercellular spaces, inducing cell hyperplasia, leading to rupture of the leaf epidermis and resulting in raised corky and spongy lesions surrounded by a water-soaked margin, that is, the characteristic canker lesion. Yellowish chlorotic rings are also often observed on leaves and fruits and, when conditions are highly favorable to disease development, could produce general defoliation, tree decline, and premature fruit drop [48, 49].
There are three different forms of citrus canker produced by two species of
4. Quorum sensing in Xcc
Recognition of altruistic behavior, as those actions that increase the adaptation of another individual, their own cost, is a major challenge for evolutionary biologists because natural selection seems to favor selfish and uncooperative individuals [53]. Nevertheless, there are many examples in the animal kingdom, where this form of cooperation was successfully demonstrated. However, it is only recently that social behavior in microorganisms has been studied in relation to evolutionary theory [54]. Research over the last 20 years has expanded the view of bacteria as unicellular organisms having the ability to participate in complex social and cooperative behavior.
The development of an intercellular communication system is a hallmark characteristic that enables bacteria to colonize new habitats, adapt to environmental changes, resist host defense and antibiotic action, strengthen competitiveness, and take advantage of new food sources [55]. This talent for cooperative multicellular behavior depends on the implementation and recognition of diffusible signal molecules by a system known as quorum sensing (QS). Functionally, QS is a signal translation mechanism to coordinate the expression of genes at the population level. The process of QS relies upon the production, release, and detection of small signaling molecules termed auto-inducers (AIs). Each bacterial cell produces a basal amount of AIs, which are exported to the extracellular environment and reflect bacterial population density. At high cell densities, the AIs reach a critical concentration, at which point they are recognized by their cognate receptor, triggering a cascade of biological functions [56]. Bacteria within the genus
The QS system in Xcc as well as in other species that comprise the
DSF detection and transduction in bacteria involve a complex kinase sensor positioned in the cytoplasmic membrane, which is associated to a cytoplasmic regulator. The best studied of these systems is RpfCF/RpfG of
Responsible residues for DSF bond are not known yet. It is assumed that the binding of signal molecule triggers RpfC auto-phosphorylation, within the histidine-kinase domain, followed by phosphorelay, involving an aspartic acid residue in the REC domain and a histidine residue in HPT domain, and finally the transfer of one phosphate group to the REC domain in RpfG regulator [59]. The phosphorylation of RpfG enables its activation as a cyclic di-GMP phosphodiesterase, resulting in modifications in the level of cyclic di-GMP in the cell affecting the synthesis of virulence factors such as extracellular enzymes, EPS, biofilm dispersal, and motility [60].
Mechanistic detailed studies have been revealed that RpfG the regulator of DSF signaling cascade, it has Che-Y like receiver domain (REC) connected to a HD-GYP domain, which has phosphor diesterase activity, which acts on the degradation of the second messenger cyclic di-GMP (Figure 2). As outlined above, the perception of DSF in a RpfC Xcc is bound to the phosphorylation of HD-GYP domain in the RpfG regulator, and the consequent changes in intracellular second messenger cyclic di-GMP trigger major changes in bacterial phenotype [61].
Diverse pathways subsequently act to control different subgroups of virulence functions under the regulation of Rpf. The physical interaction of RpfG with two proteins with a diguanylate cyclase (GGDEF) domain acts to control motility but does not influence extracellular enzyme synthesis or biofilm formation; these two events require the conserved GYP motif in the HD-GYP domain of RpfG and are determined by DSF signaling [59]. The effect of RpfG in the synthesis of extracellular enzymes and biofilm formation could be carried on through the cyclic di-GMP influences on the global transcriptional activator Clp (cAMP receptor-like protein), which contains nucleotide- and DNA-binding domains [62]. At physiologically relevant levels of cyclic di-GMP, the global transcriptional activator Clp remains bound to cyclic di-GMP by nucleotide, avoiding the binding of Clp to the gene promoters that encode for several virulence and adaptation factors. However, when the HD-GYP domain is phosphorylated as a consequence of DSF perception, the HD-GYP domain starts its phosphodiesterase activity over cyclic di-GMP and relieves the Clp inhibition. Therefore, Clp binds to the gene promoters of several virulence factors, that is, extracellular enzymes, iron uptake, and adhesion synthesis [57]. Two transcription factors were identified to be directly regulated by Clp, that is, FhrR which regulates the expression of genes that encode flagellar, Hrp, and ribosomal proteins, the second transcription factor identified was Zur (Zinc uptake regulator), which is implicating in the regulation of multidrug resistance, iron uptake, and detoxification [63]. DSF also regulates the expression of
5. Virulence factors affected by quorum quenching in Xcc
Quorum sensing helps to coordinate bacterial behavior based on community, but it is not essential for the survival of bacteria. Therefore, the inhibition of QS only disrupts phenotypic traits that could be targets for the control of diseases, such as virulence, biofilm formation, and bacterial resistance to several antibiotics. QS interference could involve signal degradation (quorum quenching) or signal overproduction (pathogen confusion) [64, 65]. Quorum quenching is a mechanism adopted by a number of bacteria to disrupt QS signaling of competitors, affording these organisms an advantage within a particular habitat. A recent study has shown that bacterial members of the autochthonous microbiota of citrus leaves displayed a great ability to disrupt quorum sensing in Xcc, thus drastically reducing the symptoms and severity disease of citrus canker in susceptible host [66].
The bacterium Xcc has evolved a regulatory system to adapt the expression of virulence factors. As mentioned above, the
The DSF/Rpf QS system is also prerequisite for the full virulence of Xcc after entering the host, at the mesophyll tissue. Deletion mutants rpfF,
6. Conclusions
Inhibition of quorum sensing can lead to certain phenotypic alterations, such as virulence reduction, reduced biofilm formation, and increased bacterial sensitivity to treatments. All these traits have implication in a severe symptomatology reduction. Interruption of DSF signaling in
Because QS or cell-cell signaling control processes associated with virulence of many pathogens, interference with these processes may afford a route toward disease control. Such interference could involve signal degradation (quorum quenching) or signal overproduction (pathogen confusion). Design and implementation of strategies to disrupt QS in Xcc may represent a highly valuable tool in the process of biological control and offer an alternative to the traditional copper treatment currently used for the treatment of citrus canker disease, with significant environmental, economic, and health implications worldwide.
Acknowledgments
The authors are grateful to the Sao Paulo Research Foundation (FAPESP), Grant 2015/22473-3.
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