**3.2 C-type lectin receptors**

CLRs (C-type lectin receptors) are a diverse restriction protein family defined by the presence of an extracellular carb acknowledgment space (CRD) or a C-type lectin like area (CTLD) [99]. The job of CLRs in antifungal insusceptibility has been the subject of serious investigation as of late and a few key CLRs have now been shown to show basic capacities in Candida acknowledgment, take-up, and executing and furthermore add to the commencement and additionally tweak of the resistant reaction to organisms [46, 100, 101]. By and by, the key CTLs in Candida affirmation appear, apparently, to be dectin-I, dectin-2, and MR. CLRs signal through incitation of ITAM/ITIM (immunoreceptor tyrosine-based actuation/restraint theme) cytoplasmic areas (**Figure 3**). This can be done by using their own cytoplasmic area, as dectin-I does, or by using coreceptor cytoplasmic spaces, as DAPI2 (DNAX actuation protein of I2 kDa) and FcR (Fc receptor gamma chain) do, as dectin-2 does. The activation of numerous connections to those activated

#### **Figure 3.**

*Signaling and damage pathways activated by* C. albicanshyphae. C. albicanshyphal *cells, when in sufficient quantities, are recognized by an unknown PRR mechanism that results in the activation of NF-B, MAPK, and PI3K pathways. MAPK signaling via p38 and ERK1/2 appears to discriminate between yeast and hyphal cells. Activation of p38 by hyphae leads to activation of the c-Fos transcription factor, which, in conjunction with the p65/p50 NF-B heterodimers and PI3K/AKT results in upregulation of cytokine and inflammatory mediator expression. Concurrently, activation of ERK1/2 signaling, results in stabilization of the MKP1 phosphatase, which deactivates p38 and JNK, hence acting as part of a negative feedback loop and preventing a potentially deleterious overreaction of theimmune system. Damage induced by hyphae appears to be mediated via JNK activation and prevented via the PI3K/AKT/mTor pathway.*

#### *Pathogenicity Mechanism of* Candida albicans *DOI: http://dx.doi.org/10.5772/intechopen.99737*

by TLRs, most notably Src family kinases including Src, Lyn, and Fyn, is triggered when CLRs are ligated. If we talk about dectin-I , it prompts initiation of spleen tyrosine kinase (SYK) and the downstream actuation of the CARD9/BclI0/MALTI (caspase enlistment space family/B cell CLL-lymphoma I0/mucosa related lymphoid tissue lymphoma movement quality I) flagging complex. Independent of the CLR pathways and connectors utilized, a definitive outcome is the enactment of comparative flagging pathways as those initiated by TLRs, overwhelmingly NF-B and MAPK, that are discussed below point.

### *3.2.1 Dectin-I*

Dectin-I, (also called CLEC7a) is that the main CLR known as taking part in a serious role in fungous recognition by the host system [102] and may be a sort II transmembrane macromolecule that belongs to a subgroup of CLRs referred to as natural killer (NK) receptor-like CLRs. The target ligands of dectin-I are -I,3 glucan polymers, that comprise a serious part (∼60%) of fungous cell walls. The intracellular region of dectin-I contains a changed ITAM motif containing one amino acid residue rather than the standard 2 (hence the terms hem-ITAM or hemi- ITAM). Activation of the dectin-I results in phosphorylation of this domain and phosphorylation of SYK and activation of the BclI0- CARD9-MALTI complicated as mentioned on top of. This results in activation of each the canonical and noncanonical NF-B pathways [103] further as nuclear issue of activated T cells (NFAT) pathway [104]. Dectin-I can even induce signaling via Raf-I in an exceedingly SYK -dependent fashion [103] and is related to phospholipase C and A2 activation [50]. one in all the most important functions of dectin-I binding seems to be the induction of bodily process [105]. However, a singular feature of dectin-I is its ability to be activated or suppressed by its target matter. to completely activate dectin-I, cells got to be exposed to insoluble -glucan particles. Notably, exposure of dectin-I to soluble -glucan seems to dam activation. This appears to ensue to the apparent form type a vegetative cell conjunction,"whereby phosphatases that usually suppress ITAM motifs are accumulated. This exclusion later permits the phosphorylation of the intracellular hem-ITAM motif [106], thereby sanctioning bodily process. Dectin-I has additionally been shown to synergise with each TLR2 and TLR4, leading to the induction of tumor necrosis factor (TNF), IL-I0, transforming growth factor (TGF) and dendritic cell maturation [107–109]. In view of the fact that the - I,3 glucan polymers that are the main components of the fungal cell wall, and a strong activation of the immune system, dectin-I plays an important role in inducing antifungal activity of the host. This may also explain why some of the mold surface structure of "the mask" -I.3 glucan from the immune system. For example, Histoplasma capsulatum, masks are -I,3 glucan, with a low - -I,3 glucan [110] and it seems likely that the *C. albicans* hyphae of -I,3 glucan has been covered over by layers of - - linked mannoproteins in order to prevent the discovery of the dectin-I. However, the yeast is in the form of *C. albicans*, while - - linked mannoproteins present in the underlying -glucan layer is exposed in the developing gut, which dectin-I in order to be recognized. Thus, it could be concluded that the most important role of dectin-I in the control of the yeast form of candidiasis (thrush). In addition, - glucan, which has been in the hyphal cell wall of *C. albicans*, it seems to be structurally different from the yeast - glucan [111] and, therefore, may not be immune to or understood by the dectin-I.

Although some studies have shown that the expression of dectin-I in the epithelial cells of the gastro- intestinal tract [112], and lung [113, 114], in oral epithelial cells express dectin-1 [115, 116]. What's interesting is that dectin-I expression

appears to be reduced in the presence of live *C. albicans* cells [116], and it is not affected by the dectin-I ligands [115, 117]. This suggests that dectin-I is likely to play only a minor role in the detection of *C. albicans* epithelial cells. Studies carried out with the help of dectin-I knockout mice have provided mixed data sets for the *C. albicans* systemic infection models, to demonstrate these differences, [118] and increased mortality [119] depending on the study, the *C. albicans* strain used. On the one hand, it is the work for the dectin-I is supported by the consideration that CARD9 knockout mice are susceptible to the most important infection [120] and in patients with head-and-CARD9 immunity and are particularly vulnerable to both the lining and the main foundation candidiasis [121]. In addition, another study, it has been the study of the normal function of the genetic polymorphism in CARD9 (SI2N), to CADR9, especially candidiasis, it is recommended that the method of fixing of the - glucan may be excessive for the first invulnerability of *C. albicans* [122]. However, recent studies have shown the potential role of dectin-I in the maintenance of tissue health. Dectin-I−/− the mice showed greater severity of the disease, at least one more commonly, however, this weight can be reduced by the removal of fungal and bacterial flora in [123]. Histologically, extensive infestations of fungi have been recorded from the underlying tissue, which was not seen in wild-type mice. Clinical trial data have shown that a subgroup of patients with ulcerative colitis, especially in aggressive disease, and shows a common singlenucleotide polymorphisms (rs2078I78 in dectin-I, possibly indicating a requirement for functional dectin-I receptors, and to maintain, mucosal health, in a commensal state [123]. However, the role of dectin-I in the intramucosal infections, it is far from clear, as recent studies in mice have demonstrated that dectin-I does not play an important role in the control of gastro-intestinal colonization by *C. albicans* [124]. In particular, it is well known that, in humans, mutations in the stop codon (Tyr238X in dectin-I is associated with an increased risk of developing mucocutaneous fungal infections, with an increased colonization of the oral cavity and the gastrointestinal (gi) tract and vulvovaginal candidiasis (thrush) infection (RVVC) [125, 126]. In another case, we obtained that the dectin-I polymorphism (I223S) was associated with oropharyngeal candidiasis (OPC) the susceptibility of West Africa, a group of HIV-positive patients [127]. That is why, even though the great one, the precise role of dectin-I in the susceptibility to candida infection is still unclear and requires further investigation.

#### *3.2.2 Dectin-2*

Dectin-2 (otherwise called CLEC6a) is a sort II transmembrane protein however is enacted contrastingly to dectin-I. Dectin-2 comes up short on an intracellular flagging area [128] and requirements to dimerise with FcR, which has an intracellular flagging space, to send a sign [69]. In myeloid cells and fiery monocytes, dectin-2 perceives high mannose structures that are normal to numerous parasites and ties to hyphae with higher proclivity than to yeast [129, 130]. This may clarify why dectin-2 inadequate mice are helpless to *C. albicans* contamination be that as it may, strangely, not *C. neoformans* [130, 131]. Dectin-2 may moreover recognize -mannosyl linkages [132]. Dectin-2 may activate a number of cytokines and chemokines via NF-B, MAPK, SYK, CARD9-BclI0-MaltI, and PKC, as well as initiate the NLRP3 (NOD-like receptor family, pyrin region containing 3) inflammasome and a respiratory burst [69, 133]. Furthermore, dectin-2 may have a role in protecting against *C. glabrata* illnesses, since dectin-2/lacking mice were more susceptible to *C. glabrata* infections, indicating a poor transmittable choice in kidneys [134].

## *3.2.3 Dectin-3*

Dectin-3 (additionally called CLECsf8, MCL, or CLEC4d) was as of late distinguished and seems to shape heterodimers with dectin-2 to perceive -mannans on the outside of *C. albicans* hyphae, prompting NF-B enactment [135]. Strikingly, dectin-3−/− mice were exceptionally helpless to *C. albicans* disease. Contrasted and their particular homodimers, dectin-2/3 heterodimers bound -mannans all the more viably, prompting strong incendiary reactions. This recommends that distinctive CLRs may shape an assortment of hetero and homodimers that may give diverse affectability and variety to have cells to identify different contagious contaminations.

## *3.2.4 DC-SIGN*

DC-SIGN (otherwise called CD209) is another sort II transmembrane receptor that is communicated dominatingly on dendritic cells and macrophages. Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) also known as CD209 (Cluster of Differentiation 209) is a protein which in humans is encoded by the CD209 gene. DC-SIGN is a C-type lectin receptor present on the surface of both macrophages and dendritic cells Nonetheless, the part of DC-SIGN in antifungal invulnerability is muddled [101], in spite of the fact that DC-SIGN seems to perceive high (-connected) mannose containing glycoproteins and actuate IL-6 creation [71, 136]. Albeit the part of DC-SIGN in the endocytosis and take-up of microbes to advance antigen show is all around recorded [136, 137], its job in phagocytosis is sketchy [71, 136].

## **3.3 Mannose receptor**

The MR (or called CD206) is a prototypical kind I transmembrane protein that is transcendently communicated on macrophage and dendritic cells. MR receptor ties a few starch particles, including extended -connected mannans, N-acetylglucosamine, glucose, and fucose [138]. Thus, MR can perceive numerous contagious, bacterial, and viral pathogens. MR needs regular intracellular flagging spaces despite the fact that ligation actually prompts an assortment of cell reactions, including signal pathway acceptance, phagocytosis, advancement of antigen show to T cells, and cytokine discharge [63, 136–140]. For instance, the MR is enlisted to the phagosome after *C. albicans* ingestion and actuates intracellular flagging and cytokine creation [141]. MR may likewise be needed for the enlistment of defensive ThI7 reactions in *C. albicans* contamination [140] however may repress cytokine creation because of different organisms, for instance, Pneumocystis carinii [142]. Remarkably, MR inadequacy does not seem to present helplessness to *C. albicans* foundational disease [143] as it does to *C. neoformans* [144], albeit minor changes in parasitic weights can be noticed [143]. In oral epithelial cells, MR impeding does not modify the discharge of IL-6, IL-8, and GM-CSF upon incitement with Candida cell divider parts [117]. As of now, there is no conclusive part for MR in mucosal antifungal host safeguards.
