List of major PRRs involved in recognition of various fungal-derived PAMPs.
Abstract
For a fungal pathogen to successfully infect, colonize and spread inside a susceptible host, it must have overcome the host immune responses. The early recognition of the fungal pathogen-associated molecular patterns (PAMPS) by the host’s pattern recognition receptors (PRRs) results in the establishment of anti-fungal immunity. Although, our immune system has evolved several processes to combat these pathogens both at the innate and adaptive immune levels. These organisms have developed various escape strategies to evade the recognition by the host\'s innate immune components and thus interfering with host immune mechanisms. In this chapter, we will summarize the major PRRs involved in sensing fungal PAMPS and most importantly the fungal tactics to escape the host\'s innate immune surveillance and protective mechanisms.
Keywords
- PAMPs
- PRRs
- innate immunity
- escape mechanisms
- pathogenic fungi
1. Introduction
Pathogenic fungi are an important cause of morbidity and mortality in humans particularly in immune-compromised individuals [1, 2]. The most common risk factors for the increased incidence of fungal infections in immunocompromised individuals are cancer therapy, use of corticosteroids and neutropenia [3, 4, 5]. Sporadic occurrence of fungal infections has also been described in immunocompetent individuals that have undergone any traumatic inoculation such as the use of catheters or surgeries [6, 7]. Fungal pathogens show a considerable variation in their biology and disease pathogenesis and may include opportunistic fungi, i.e.,
The human innate immune system is the first line of defense and plays a pivotal role in the body’s defense on confrontation to the invading pathogens. One of the fundamental responses towards the infectious agents including fungi is the inflammatory response that is launched immediately by the host body following an immunological insult. This inflammatory response drives the antigens specific adaptive immune response such as activation of antigen-specific lymphocytes against the invading pathogens. The innate immune system recognizes a particular set of conserved surface molecules exhibited by the pathogens called pathogens-associated molecular patterns (PAMPs). Host cell pattern recognition receptors (PRRs) detect microbial PAMPs and trigger the intracellular signaling pathways that lead to the production of cytokines, reactive oxygen species (ROS), reactive nitrogen species (RNS), and lipid mediators [8, 9]. Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) are the most common PRRs characterized for the detection of fungal PAMPs. Microbial detection by these PRRs results in a cascade of signaling events that eventually result in the production of inflammatory mediators, phagocytosis and induction of adaptive immune response [10]. However, fungal pathogens have adapted simple yet innovative strategies to evade and/or counteract the host innate immune responses thus resulting in the establishment of a successful infection inside the host. In the current chapter, we have made a comprehensive understanding of the major innate immune receptors involved in the detection of the fungal pathogens as well as the strategies employed by the pathogenic fungi to evade and therefore enhance their viability inside the host during infection.
2. Innate immune recognition of fungal PAMPs by host PRRs
2.1 Role of TLRs in recognition of pathogenic fungi
TLRs are a family of receptors that share structural homology with the Toll receptor (first described in the
Both TLR2 and TLR4 are involved in the innate immune recognition of fungal PAMPs (Table 1) (Figure 1) [10]. TLR4 has been described to recognize the fungal-derived mannans. Recognition of
PRRs | Fungal pathogen | Fungal PAMPs |
---|---|---|
TLR4 | O-linked mannans | |
Mannans | ||
Rhamnomannans | ||
Phospholipomannans | ||
Glucuronuxylomannans | ||
Unknown/α-, β-glucan, galactomannan | ||
Unknown | ||
TLR2/TLR6 | Phospholipomannans | |
Glucuronuxylomannans | ||
TLR2/TLR1 | Glucuronuxylomannans | |
TLR2 | Α 1,4 glucans | |
Unknown | ||
MR | N-linked mannans | |
Mannans | ||
Mannoproteins | ||
gp43 | ||
Dectin-2 | α-mannans | |
Dectin-1 | Β (1, 3)- glucans | |
DG-SIGN | Galactomannans | |
Mannans | ||
Unknown/surface carbohydrates in extracellular vesicles | ||
Mincle | Polysaccharides containing α-mannosyl residues | |
CD14 | Mannans | |
Unknown | ||
Α (1,4) glucans | ||
NLRP3 | Unknown/ β (1,3)-glucans |
Alike TLR4, TLR2 is also involved in the recognition of the fungal molecules. TLR2 triggers the activation of NF-κB and subsequent release of cytokines from the macrophages in response to phospholipomannan (a cell wall lipoglycan isolated from
It has been observed that cytokine production from macrophages and dendritic cells is mediated by TLR2 and CD14 in response to
2.2 Role of CLRs in recognition of pathogenic fungi
CLRs are a group of proteins receptors involved in the detection of fungal glycoconjugates and are characterized by the presence of two motifs; the EPN motif and QPD motifs both of which drive the specificity of CTLRs towards carbohydrate moieties. The EPN motif helps in the recognition of mannose, N-acetylglucosamine, glucose and L-fucose whereas the QPD motif is involved in the recognition of N-acetylgalactosamine and galactose [27, 28, 29, 30, 31]. The major CTLRs implicated in the recognition of fungal molecules are Dectin-1, Dectin-2, Mannose receptors (MR), Mincle, DC-SIGN, CD-12, and CD-11b/CD18 (Table 1) (Figure 1).
2.2.1 Mannose receptor (MR)
The mannose receptor is a type I transmembrane receptor that contains an N-terminal cysteine-rich domain and a type II fibronectin domain. The extracellular component of MR comprises of eight CTLDs (C-type lectin domains) whereas the intracellular component possesses a motif required for endocytic signaling [32]. MR is capable of recognizing fungal PAMPs that contain either mannose, glucose, N-acetylglucosamine [32, 33, 34], or sulfated galactose and sulfated N-acetylglucosamine (Table 1) (Figure 1). Recognition of sulfated glycoconjugates is mediated by the cysteine-rich domain of MR and is independent of CTLDs [35, 36]. On the other hand, recognition of mannose-based fungal PAMPs is dependent on the activity of CTLDs (mostly 4–8) [34]. Several fungal pathogens can be detected by MR including
Besides its role in endocytosis, MR also contributes to the production of cytokines in response to glycoconjugates comprising mannans [15, 40, 41]. On recognizing the
2.2.2 Dectin-2
A transmembrane protein that was first characterized in a cell line derived from Langerhans cells. Dectin-2 is comprised of a short cytoplasmic domain and an extracellular domain with CLTD present in the COOH-terminal region. Activation of Dectin-2 by the fungal ligands leads to the production of eicosanoids and cytokines [44, 45, 46]. Usually, macrophages, some dendritic cells and IL-6/IL-23-stimulated neutrophils express Dectin-2 receptors [45, 47, 48]. The EPN motif present in the extracellular domain of Dectin-2 recognizes fungal glycoconjugates containing mannose and fucose (Table 1) (Figure 1) [47]. The binding of Dectin-2 to zymosan requires Ca2+, however, higher concentrations of mannose, fucose, glucose, galactose and N-acetylglucosamine can inhibit this binding. Dectin-2 shows a higher binding affinity towards synthetic carbohydrates that are extensively mannosylated. However, the binding affinity decreases with the decrease in mannosylated residues [49]. Dectin-2 receptor recognizes
2.2.3 Dectin-1
Dectin-1 is a type II transmembrane receptor that recognizes and binds to the molecules containing β (1,3)-glucans. It is expressed by many cell types including macrophages, dendritic cells, eosinophils and neutrophils [52, 53, 54]. Dectin-1 mediated signaling results in the production of cytokines [55], maturation of dendritic cells [56] and production of ROS [57]. This suggests that Dectin-1 is an important PRR in recognizing β (1,3)-glucans followed by leukocytes activation and induction of adaptive immunity. However, in contrast to many other CTLRs, Dectin-1 binding to β-glucans is not dependent on Ca2+ [58, 59]. Dectin-1 possesses higher specificity towards β (1,3)-glucans having β (1,6)-branches. On the other hand, Dectin-1 is unable to bind with mannans, pullulans, β1,6-glucans or β (1,3)/(β1,4)-glucans [58]. In contrast to TLRs which recognize soluble ligands, activation of Dectin-1 is dependent upon its clustering by the β-glucans molecules followed by exclusion of tyrosine phosphatases (CD45 and CD48) and phosphorylation of hemi-ITAM motif present in the cytoplasmic tail of Dectin-1 [60, 61]. The hemi-ITAM recruits Syk kinases and initiates the upstream signaling pathway leading to the activation of NF-κB and NFAT [60, 62]. Usually, alveolar macrophages (AMs), resident peritoneal macrophages and dendritic cells present Dectin-1 dependent responses towards β-glucans while bone marrow-derived macrophages do not. However, Dectin-1 dependent responses can be promoted in non-responding cells such as bone marrow-derived macrophages in the presence of IFN-γ and GM-CSF thus suggesting that responses mediated by Dectin-1 are flexible [63, 64].
2.2.4 Mincle
Also known as CLEC4E is a type II transmembrane protein that was first identified as a macrophage-expressed gene dependent on the activity of the NF-IL6 transcription factor [65]. It is composed of a short cytoplasmic tail with an extracellular domain containing a CLTD. Mincle triggers cell signaling by recruiting the FcRγ chain which leads to the activation of NFAT and NF-κB and eventually induces transcription of cytokines [66]. Like other CTLRs, Mincle also plays an important role in the recognition of fungal molecules (Table 1) (Figure 1) [67, 68]. Soluble Mincle has been described to interact with
2.2.5 DC-sign
A type II transmembrane receptor with extracellular domain containing one CRD in its COOH- terminal and an and extracellular stalk. The stalk is comprised of seven residues that aid in DC-SIGN oligomerization [70, 71]. The CRD of DC-SIGN contains an EPF motif. DC-SIGN binds to glycoconjugates containing mannans and fucosylated carbohydrates in the presence of Ca2+ [72]. Both macrophages and dendritic cells express DC-SIGN. It is an endocytic receptor that can recognize and internalize several fungal pathogens followed by their release in the endosomal vesicles [73, 74]. In response to mannose-containing ligands, DC-SIGN has been described to enhance the cytokine production induced by the TLRs whereas fucosylated ligands amplify the IL-10 while inhibiting the production of proinflammatory cytokines. Mannosylated lipoarabinomannans (ManLAM) mediated activation of DC-SIGN results in inhibition of dendritic cells maturation by the LPS [75]. Thus, some pathogens infecting the dendritic cells can escape the immune activity by activating and inhibiting the DC-SIGN mediated maturation of dendritic cells. Thus, activation of DC-SIGN seems to exhibit complex effects such as internalizing the pathogens, triggering cytokine production and restricting the maturation of dendritic cells [76].
DC-SIGN has been involved in the recognition of many fungal pathogens including
2.3 CD11b/CD18 (MAC-1, CR3)
CD11b/CD18 also recognized as CD18 is a heterodimer receptor comprising of type I protein chains; αM chain (CD11b) and the common chain CD18 both of which are attached non-covalently. CD11b/CD18 is expressed by many of the leukocytes such as neutrophils, eosinophils, monocytes, macrophages and NK cells [80]. CD11b/CD18 helps in the adhesion of leukocytes to the activated endothelium and phagocytic receptors for antigens opsonized with iC3b [81]. In addition, CD11b/CD18 is also involved in the detection of β (1,3)-glucans. The αM chain of CD11b/CD18 possesses two distinct domains; the I-domain and a lectin domain. The I-domain binds ICAM-1, iC3b and fibrinogen whereas the lectin domain recognizes the fungal glycoconjugates such as β (1,3)-glucans, glucose, mannose and N-acetyl-D-glucosamine [82]. CD11b/CD18 triggers ROS production from neutrophils and macrophages in response to
2.4 CD14
A glycosylphosphatidylinositol-anchored protein receptor was initially considered as an LPS binder. The Cd14 receptor is comprised of an extracellular domain containing cysteine-rich residues that form a horseshoe-like conformation [87, 88, 89]. Although, the CD14 receptor does not contain intracellular regions, however in cooperation with TLR2/MD receptors, it confers a high degree of sensitivity towards LPS [89]. CD14 has also been recognized as a co-receptor involved in TLR2- [90], TLR3- [91], TLR7- and TLR9-mediated detection of ligands [92]. Similar to the LPS, detection of mannans derived from
3. Fungal strategies of host innate immune evasion
3.1 Shielding of stimulatory PAMPs
Protecting the pathogen’s inflammatory PAMPs from recognition by the host’s PRRs is one of the most significant escape mechanisms employed by the microbes [94, 95]. PRRs, which are found in various cellular components of primitive immune cells, are capable to identify recurrent pathogenic structures called PAMPs [96]. The host usually responds
Similar to Dectin-1, Dectin-2 and Dectin-3 are also integral membrane proteins that belong to the CLRs family. Dectin-1 detects glucans, while Dectin-2/3 identifies mannans [109]. These may produce heterodimer complexes that provide greater sensitivity to host tissues as well as a high potential for binding to mannans [50]. While investigating the functions of Dectin-2 in
The α (1,3)-glucans present in the outermost layer of the cell wall helps in the pathogenicity of
The
3.2 Modulation of inflammatory signals
In respect of anti-inflammatory cytokine impact, TLR2 stimulation differentiates from TLR4 activation, with proinflammatory cytokine production being lower following TLR2 stimulation than the TLR4 stimulation [125]. TLR4 agonists selectively produced Th1-inducing cytokine signals in DCs, whereas TLR2 activation generate a more strong anti-inflammatory Th2 reaction [126]. Because each effector’s arm elicits a different immune reaction, the equilibrium between Th1/Th2 reactions is thought to be important in deciding the severity of infection [127, 128]. The Th1 pathway generates pro-inflammatory cytokines such as IFN-γ, which stimulate cell-mediated immune mechanisms such as cytotoxicity and phagocyte activation. Th1 pathway is essential in the fight against intracellular and fungal infections. The Th2 pathway is characterized by cytokines such as IL-4, IL-5, as well as IL-10 and promotes a humoral response while suppressing the Th1-dependent effector functions [129]. Th2 cytokines may decrease monocyte anti-hyphal activity as well as lead to oxidative burst amid antifungal reactions [128]. TLR2-deficient macrophages have improved anti-candidal abilities [130], and TLR2 macrophages in mice are significantly more tolerant to widespread
3.3 Shedding of decoy components
Several innate immune evasion strategies have been identified for
3.4 Persistence in the intracellular environments
Several fungal pathogens have developed the potential to avoid the phagocytic activity of macrophages. For example,
3.5 Complement evasion
The complement system is a dynamic mechanism that plays a significant part in innate immunity and antibody-mediated protection against pathogenic microbes [154]. Several foreign antigens including fungal PAMPs, cellular debris, as well as antigen–antibody complexes can activate a series of complement pathways [98, 155]. Excessive tissue damage and inflammation by the complement system are avoided by the regulatory molecules of the complement system [156]. The complement system is split into three pathways; classical, alternative and lectin pathway. The activation of all these pathways varies in regards to associated components but all pathways submerge by producing the same group of effector molecules, i.e., opsonization and formation of membrane attack complex (MAC) [96]. All complement mechanisms contribute to the production of C3 convertase as well as the C3b fraction, which in turn promotes the synthesis of C5 convertase. C5 convertase cleaves the C5 factor into C5a and C5b. The distal complement components are formed as a result of a succession of accumulation and polymerization processes, as well as the mobilization of terminal complement elements such as C6, C7, C8, and C9. The terminal complement components form MAC causing cell lysis by inserting C9 into the lipid membrane layer [157, 158, 159]. Pathogenic organisms, on the other hand, have adopted different approaches to evade complement attacks, such as binding to regulatory complement proteins by secreting proteases or evading opsonization. For example,
4. Conclusion
Our understanding regarding the innate immune recognition of pathogenic fungi by the corresponding fungal PAMPs is still poor. Moreover, the fungal ligands involved in the activation of host PRRs remain largely unknown for several pathogenic fungi. Characterization of fungal PAMPs and their recognition by the host PRRs can provide a comprehensive understanding of pathogenesis and immunity to the pathogenic fungi. In addition, characterization of these fungal ligands and their activation of respective PRRs is essential not only to discover new therapeutic approaches against fungal infections particularly in immune-compromised patients but also to develop novel adjuvants for enhancing the prophylactic immune responses against pathogenic fungi.
Acknowledgments
The author would like to acknowledge all the co-authors for their contribution.
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