Next Article in Journal
A Venom Allergen-Like Protein, RsVAP, the First Discovered Effector Protein of Radopholus similis That Inhibits Plant Defense and Facilitates Parasitism
Next Article in Special Issue
Development of a Highly Sensitive β-Glucan Detection System Using Scanning Single-Molecule Counting Method
Previous Article in Journal
Synergistic Effect of Methyl Jasmonate and Abscisic Acid Co-Treatment on Avenanthramide Production in Germinating Oats
Previous Article in Special Issue
Variation, Modification and Engineering of Lipid A in Endotoxin of Gram-Negative Bacteria
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 22
Issue 9
10.3390/ijms22094778
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Insights on the Functional Role of Beta-Glucans in Fungal Immunity Using Receptor-Deficient Mouse Models

by
Mark Joseph Maranan Desamero
1,2,
Soo-Hyun Chung
3 and
Shigeru Kakuta
1,*
1
Laboratory of Biomedical Science, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
2
Department of Basic Veterinary Sciences, College of Veterinary Medicine, University of the Philippines Los Baños, Laguna 4031, Philippines
3
Division of Experimental Animal Immunology, Research Institute for Biomedical Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(9), 4778; https://doi.org/10.3390/ijms22094778
Submission received: 29 March 2021 / Revised: 21 April 2021 / Accepted: 27 April 2021 / Published: 30 April 2021
(This article belongs to the Special Issue Diagnostic Challenge and Therapeutic Approaches in Human Sepsis Based on the Appearance of Endotoxemia and Beta-D-Glucanemia)
Browse Figures
Review Reports Versions Notes

Abstract

:
Understanding the host anti-fungal immunity induced by beta-glucan has been one of the most challenging conundrums in the field of biomedical research. During the last couple of decades, insights on the role of beta-glucan in fungal disease progression, susceptibility, and resistance have been greatly augmented through the utility of various beta-glucan cognate receptor-deficient mouse models. Analysis of dectin-1 knockout mice has clarified the downstream signaling pathways and adaptive effector responses triggered by beta-glucan in anti-fungal immunity. On the other hand, assessment of CR3-deficient mice has elucidated the compelling action of beta-glucans in neutrophil-mediated fungal clearance, and the investigation of EphA2-deficient mice has highlighted its novel involvement in host sensing and defense to oral mucosal fungal infection. Based on these accounts, this review focuses on the recent discoveries made by these gene-targeted mice in beta-glucan research with particular emphasis on the multifaceted aspects of fungal immunity.

1. Introduction

Throughout the past decades, studies that focus on the carbohydrate-rich chemical compounds that are elaborated by food components and organisms have become a mainstay of intense scientific pursuits. Notably, beta-glucans, defined by a backbone of β-(1,3)-D-glucose with interspersing side chains made up of β-(1,6) glycosidic linkage, have commanded great attention due to their broad biofunctional activities including anti-infective [1,2], anti-tumor [3,4,5], anti-inflammatory [6,7], prebiotic [8], antioxidant [9], immunomodulatory [10,11], and blood glucose-lowering [12], among others. Beta-glucan are obtained from diverse sources such as plants, cereals, algae, bacteria, and fungal entities, producing highly divergent biological effects owing to disparity in physicochemical properties; namely, tertiary configuration, solubility, length of polymer, molecular weight, and degree of branching [13,14]. At present, a growing list of beta-glucan preparations has been a subject of human clinical trials [15,16].
Biosensing of beta-glucans and other pathogen associated molecular patterns (PAMPs) is primarily reserved to a constellation of germ line-encoded molecules called pathogen recognition receptors (PRRs), which include the archetypal toll-like receptors (TLRs), as well as the non-TLR receptors, namely the C-type lectin receptors (CLRs), RIG-like helicases, cytosolic DNA sensors, and NOD-like receptors (NLRs) [17,18]. Interests in dissecting the underlying molecular mechanism of beta-glucans have resulted in concerted efforts to delineate its potential cognate receptors. Early studies have principally focused on in vitro transfection experiments using cells ectopically expressing PRRs [19,20]. However, in the advent of gene targeting technologies [21], many investigators have taken advantage of the utility of beta-glucan receptor-deficient mouse models. Analysis of these gene-targeted mice has addressed the limitations imposed by using unpurified beta-glucan-containing materials such as the presence of contaminating microbial endotoxins (LPS) and, more importantly, underpins the direct involvement of the beta-glucan signaling pathway in disease resistance, progression, and susceptibility. Here, we summarized the prevailing knowledge and recent discoveries in beta-glucan research, wherein we highlighted the utility of selected gene modified mice generated by our colleagues and others, and the compelling role they played in uncovering the functional contribution of beta-glucan and its signaling cascade in fungal immunity and resistance.

2. Major Receptor

2.1. Dectin-1 and Signaling Cascade

Among the different PRRs, dectin-1 has been universally regarded as the principal receptor for beta-glucans [22,23,24,25,26]. Dectin-1 was first identified by a subtractive cloning in XS52 dendritic cell (DC) line [27] and is encoded by the Clec7a gene whose loci are located in a CLR gene cluster on chromosome 6 in mice and on chromosome 12 in humans [28]. It is a 43-kDa type II transmembrane glycoprotein with a single terminal CRD in the extracellular domain, which shows highly conserved structure of CLR family proteins [29], such as Dectin-2, DCIR, oxidized LDL (LOX) receptors, and asialoglycoprotein receptors (hepatic lectin 1&2) [27,30]. However, unlike others, dectin-1 has an immunoreceptor tyrosine-based activation motif (ITAM)-like motif in its intracellular domain, and lacks critical residues engaged in Ca2+-dependent carbohydrate binding processes [22,31]. Although the degree of concordance at the amino acid level between human and mouse dectin-1 is determined to be around 64% [30], their structural and functional properties are homologous [32].
Dectin-1 is highly expressed in lymphoid organs [31]. Contrary to earlier belief that dectin-1 is expressed almost exclusively by dendritic cells [27,33], recent investigations have elegantly elucidated that a broader variety of immune cell populations exhibit dectin-1 expression. In particular, several myeloid lineage cells such as peripheral blood neutrophils as well as peripheral and bone marrow-derived monocyte/macrophages displayed a strong dectin-1 expression, whereas there was a remarkably lower level on dendritic cells, resident peritoneal macrophages, and T cells in the spleen [26,34]. On the other hand, non-immune cells, such as alveolar epithelial cells, intestinal epithelial cells, fibroblasts, and endothelial cells, were also reported to express dectin-1 [18,22,35,36].
Drawing from the seminal work of Czop et al. [37], subsequent studies have gradually unraveled the complexities of the dectin-1 signaling pathway. Beta-glucans locate preferentially on discrete budding regions of the fungal cell wall [38,39]. Dectin-1 binds to beta-glucan with a high affinity, and then an activation signal is sent through the ITAM-like motif (hemi-ITAM) in its cytoplasmic tail, causing phosphorylation of its tyrosine residues [19,40] (Figure 1). Spleen tyrosine kinase (Syk) is then recruited to the ITAM-like motif via direct interaction between the phosphotyrosine residues of the ITAM-like sequences and the two tandem SRC homology 2 (SH2) domain of Syk [19,41]. As a consequence, Syk undergoes phosphorylation and mediates internalization of beta-glucan-enriched fungal components in DC [42,43]. Afterwards, an activation signal is then transmitted to the so-called caspase recruitment domain 9 (CARD9), a scaffold molecule that exclusively binds to B-cell lymphoma 10 (BCL10) and forms a trimolecular complex with BCL10 and mucosa associated lymphoid tissue 1 (MALT1) [44]. This complex enables bridging of the initial signaling events (beta-glucan/dectin-1/Syk) to the downstream activation of p65 and c-Rel subunits of the NF-κB transcription factor, ultimately leading to the biosynthesis of pro-inflammatory cytokines and induction of a series of anti-fungal responses [45]. Aside from this, Dectin1/Syk/CARD9 axis has also been implicated in the generation of reactive oxygen species (ROS), release of proinflammatory cytokine IL23, maturation of DC, and differential induction of Th1 and Th17 cells [32,42,46]. Alternatively, Dectin1/Syk/CARD9 axis may stimulate a noncanonical NF-κB route by acting on the subunit RelB, which negatively regulates polarization towards the Th1 and Th17 differentiation systems [47] (Figure 1B).
Downstream signal transduction of dectin-1 has been reported to be influenced by interaction with other innate immune receptors [48]. For instance, dectin-1 is able to collaborate with Toll-like receptor 2 (TLR2) to amplify the NF-κB-initiated release of cytokines like TNF-α, IL-10, IL-6, and IL-23 while it may integrate with other TLRs (TLR3, TLR7) to depress IL-12 induction in both DC and macrophages [32,49] (Figure 1C). Interestingly, dectin-1 can also promote a number of divergent signaling systems in a Syk-independent manner pathway and this involves cues emanating from a number of divergent signaling systems like Raf-1 and calcium-mediated pathways. Raf-1 kinase triggers the phosphorylation of the ser276 residue of the p65 subunit prompting RelB deactivation as it forms dimer with p65, the net outcome of which is complete abolition of the functional RelB-p52 DNA dimer [47] (Figure 1B). Since Raf-1 signaling similarly trickles down to NF-κB activation, there is a commensurate augmentation of Th1- and Th17-mediated activity. Meanwhile, dectin-1 may target a calcium-dependent system by switching on the calmodulin-dependent kinase II (CaMK)-proline-rich tyrosine kinase II (Pyk2) pathway (Figure 1C). This in turn relays signal, which harness the activation of ERK-MAPK to the elicitation of oxidative burst, stimulation of cAMP response element binding protein (CREB), and production of IL-10 cytokine [50] (Figure 1C). Recently, dectin-1 has been found to engage membrane-associated proteins such as the integral membrane protein, tetraspanins, and cooperatively induced anti-fungal and anti-cancer immunity. CD82, a member of tetraspanins also known as Kai1, colocalizes with dectin-1 and forms a cluster when dectin-1 binds beta-glucan, which promotes anti-fungal resistance through Syk-dependent release of pro-inflammatory cytokines and ROS [51] (Figure 1D) (Table 1). MS4A4A, the other member of tetraspanins characteristically expressed in tumor-associated macrophages, also co-ligates with dectin-1 and mediates tumor cytotoxicity by enhancing IFN-γ production and NK cell activation [52] (Figure 1E).

2.2. Dectin-1 KO (Clec7a−/−) Mice

In an attempt to interrogate the functional involvement of beta glucans in host defense mechanisms following fungal challenge, several exploratory studies have focused on dectin-1 as the beta-glucan cognate receptor [19,32,46,74] (Table 1). Based on these lines of reports, roles of dectin-1 in anti-fungal immunity were validated under in vivo context. Taylor et al. [24] developed a dectin-1 knockout (KO) mouse, which features a prominent ablation of the Clec7a gene region spanning exons 1–3. Independently, our colleagues also generated dectin-1 KO mouse by targeting exons 1 and 2 of the Clec7a gene [25]. Both mutant animals exhibited complete omission of dectin-1 expression in myeloid cells, and revealed that recognition of beta-glucan by dectin-1 was crucial for fungal recognition, cytokine induction, and ROS production, in consonance with earlier studies [19,33].
Assessment of dectin-1 KO mice has borne more important implications in the context of opportunistic fungal mycoses. This is accentuated by the discovery of a higher degree of human gastrointestinal candidiasis in hematopoietic stem cell transplant recipient patients who carry a single nucleotide polymorphism (SNP) in Tyr238X residue of the dectin-1 gene [75,76]. Similarly, Candida albicans-infected dectin-1 KO mice manifested a massive fungal dissemination in the stomach, intestines, and kidneys, and displayed a markedly abbreviated survival along with a profoundly depressed cytokine production and trafficking of inflammatory leukocytes to the peritoneum [24,77,78,79]. In converse, our colleagues [25] did not observe an increased susceptibility of dectin-1 KO mice to invasive C. albicans infection despite administration of a titrated fungal dose (1 × 106) that is one order of magnitude higher than the lethal dose adopted in another work [24]. One logical explanation for these discrepant results is the varying strains of C. albicans used. Supporting this conjecture, Marakalala and co-workers [80] has verified that a strain-specific adaptive behavior governs the outcomes of fungal dissemination, cytokine production, and immune cell infiltration. This hinges on the differential changes in cell wall chitin composition as determined by the transcriptional regulation of chitin-related genes, which was found to be higher in ATCC18804 versus SC5314 strain-infected mice.
To date, the obligatory role of beta-glucans in fungal resistance has tremendously diversified beyond the common pathogenic fungi, C. albicans. Following infection of the pneumotropic fungi, Pneumocystis carinii, dectin-1 KO mice showed a significant decrease in ROS production and an overwhelming fungal invasion in the lung tissues [25]. Correspondingly, a significant repression of cytokine synthesis and leukocyte transmigration was found in Aspergillus fumigatus- and Coccidioides immitis-challenged dectin-1 KO mice [54,59]. Meanwhile, the role of dectin-1 was dispensable in deterring pathogenic fungal species such as Cryptococcus neoformans [53], Histoplasma capsulatum [81], and Blastomyces dermatitidis [65], suggesting that dectin-1 roles in anti-fungal immunity still have species-specificity.
Apart from fungal strain and species, it is conceivable that other factors may predict the beta-glucan-mediated host defense reaction against insulting fungi. Even though it has been recounted that mouse genetic background does not determine the response of dectin-1 KO mice to C. albicans infection [80], few accounts have attested otherwise. As illustrated by Carvalho et al. [82], dectin-1 KO mice on C57BL/6 (B6) background harbor a greater magnitude of fungal load in several mucosal organs in converse with the relatively unaltered tissue architecture in C. albicans-infected BALB/c dectin-1 KO mice. In a similar vein, B6 mice exemplified an augmented sensitivity to Coccidioides immitis infection in contrary to DBA/2 mice [83]. In both these investigations, the significant disparity in disease susceptibility between mice background was partly ascribed to absence of dectin-1 gene isoforms in BALB/c and DBA/2 mice genes [84,85], compared to the presence of splicing isoforms of dectin-1 in B6 mice. Interestingly, the major dectin-1 isoforms in humans have also been stratified according to alternative mRNA splicing wherein dectin-1A isoform carries a full length dectin-1 transcript while dectin-1B isoform contains an obliterated extracellular stalk region [31]. Detailed analysis of these isoforms showed that the significant degree of N-linked glycosylation in human dectin-1A is responsible for cell surface translocation enabling enhanced beta-glucan ligation and downstream activation of signaling pathways such as NF-κB, Akt, p38, and Ras-Raf-Mek1/2 [86]. Hence, dectin-1 isoforms may possibly serve as a useful determinant of host cellular responses versus fungal organisms.
Furthermore, factors such as infectious fungal load and organ sensitivity should also be considered. For example, A/J and DBA/2 inbred mice systemically challenged with 1 × 105 C. albicans blastoconidia were able to recuperate from Candida infection but yielded to the fatal disease when given a higher dose of 3 × 105 [87]. In a parallel sense, an incremental increase of C. albicans strain ATCC1880 inoculum up to 10 times higher than the original dose provided by our colleagues had predisposed dectin-1 KO B6 mice to a level of fungal sensitivity that is nearly tantamount to that afforded by the SC5314 strain [80].
Early experimental data in vitro have proposed that beta-glucans are deliberately exposed whenever yeast undergoes physiological budding processes [88,89]. Arguing against this concept, succeeding in vivo examinations have asserted that beta-glucans are comparably unmasked regardless of morphological types (yeast and hyphal forms) and fungal strains (SC5314 and ATCC1880) especially during the later stages of live C. albicans infection [80,90,91]. Considering the data generated by our colleagues, it seems likely that beta-glucans are not readily accessible for dectin-1 recognition after infection with live C. albicans, as shown by a decreased cytokine production of dectin-1 KO thioglycolate-stimulated macrophages. This is compatible with previous presumptions that beta-glucans are not easily extruded at the cell wall surface of live C. albicans but rather imbedded subjacent to the dense mannan-mannoprotein layer [92,93]. Likewise, in Paracoccidioides brasiliensis [94], and Cryptococcus neoformans [95], beta-glucans are concealed by an alpha-glucan and galactoxylomannan/glucoronoxylomannan-enriched external layer, respectively. Lending further justification to these lines of reports, treatment of live zymosan or live C. albicans with sodium hypochlorite (NaClO) [96], caspofungin [91] or heat-killing treatment [92,97] has dramatically improved beta-glucan exposure. However, this notion cannot be generically applied to all fungi as beta-glucans are abundantly expressed on the cell surface of live Coccidiodes spp. [59]. Recently, it has been shown that the proportion of beta-glucan surface expression is highly heterogeneous even at the strain level [98]. Hence, fungal organisms may variably organize beta-glucans on their cell wall surface to thwart recognition and stifle host innate immunity from mounting an appropriate anti-fungal response.
Beta-glucan recognition by dectin-1 and its downstream signaling plays important roles to tether fungal recognition to boost effector functions in the host immune system. As described above and confirmed by our colleagues using Sparassis crispa glucan (SCG), dectin-1-beta-glucan complex can render DCs and other antigen presenting cells to undergo maturation and activation [25]. This is followed by the release of inflammatory cytokines that can direct naive CD4+ T helper cells to adapt a specific differentiation program [99,100]. Where a cytokine milieu has a particular enrichment for IL-6, IL-1β, IL-23, and TGF-β may bias towards Th17 differentiation, the production of TNF-α and IL-12 may instruct cells to polarize into a Th1-type [46,101]. Activated DCs can also tailor the conversion of Treg cells into IL-17-secreting cells, which are produced by a hybrid population of human Foxp3+IL17+ T cells [102]. However, the mechanism whereby the host maintains Th1-Th17 balance is presently ill-defined [27]. Dectin-1 KO mice infected with Coccidiodes spp. divulged mixed Th1 and Th17 immune responses [59,103], yet neither of these adaptive differentiation modules has accorded protection in dectin-1 KO mice intraperitoneally challenged with Trichopython rubrum [64]. In invasive aspergillosis, dectin-1 Y238X polymorphism has prompted a decreased cytokine expression of IL-6, IL-17, IL-1β, IL-10, and IFN-γ in human PBMCs, suggesting a cooperative interrelation between Th1 and Th17 immunity [104]. Digressing from this observation, a paper by Werner and colleagues [54] has disputed this in favor of a predominant Th17 pathway, as hinted by the sizeable reduction of A. fumigatus clearance in dectin-1 deficient mice vis-à-vis an IL-17 blockade. Mechanistically, this perceived lineage commitment towards IL-17-producing Th17 cells has been strongly connected with a profound diminution in IFN-γ and IL-12p40 cytokine expression [56]. In human cases of mucocutaneous C. albicans infection, a markedly depleted IL-17 expression was specifically detected in patients bearing dectin-1 Y238X polymorphism [105]. A proclivity towards Th17 immunity was similarly documented in C. albicans- infected IL23p19-, IL17A- and IL17RA-deficient mice, which unveils an increased receptivity for the systemic form of candidiasis [106,107]. Combined together, an array of adaptive effector responses may be uniquely stimulated by dectin-1 depending on the offending fungal species.
The host defense mechanism may additionally opt to manipulate beta-glucan-dectin-1 signaling in light of other known bifurcations of the adaptive arm of immunity including CD8+ T cell-induced cytotoxicity and B cell-mediated antibody production [108]. Once activated by dectin-1, DCs can prime naive CD8+ T cells and bestow upon them the ability to expand and evolve into a fully differentiated cytotoxic CD8+ effector T cells that can competently release an apoptosis-related protein like perforins and granzymes. Activated CD4+ T cells, on the other hand, can prime B cells, enabling them to differentiate and secrete antibodies such as IgA and IgG [109]. Blurring these postulations, however, Drummond et al. [77] reported that dectin-1 deficiency does not alter CD8+ T cell proliferation and activation, while our colleagues demonstrated that antibody production is practically indistinguishable between dectin-1 WT and KO mice in the presence of activating sheep RBC or dinitrophenol-keyhole limpet hemocyanin [25]. On the grounds that the former generalizations were inferred mostly from human studies while the latter was derived largely from mouse studies, it can be reasoned that the obvious biological difference between host species may possibly address this incongruity. Also, in view of the fact that B-cell survival relies in part on signals originating from CD4+ T cells, defects in CD4+ T cell activation may precipitate B cell apoptosis and therefore create a deficit in antibody production [110].
Finally, beta-glucans may serve a pivotal role in preserving intestinal homeostasis by a delicate control of the intestinal tolerance toward commensal organisms like opportunistic fungal populations. As shown by previous studies, dectin-1- and CARD9-deficient mice had heightened susceptibility to dextran sulfate sodium (DSS)-induced colitis, because of the defective fungal killing by DCs and uncontrolled expansion of the commensal fungus, Candida tropicalis. [58,111]. Indeed, our colleagues have failed to detect the presence of this fungal species in their facility [61], however, when colonization of C. tropicalis was induced, severe inflammation of the colon in dectin-1 KO mice was observed that is consistent with those of Rahabi and colleagues’ report [112] (Figure 2).
Taken together, these accumulating lines of evidence ascertained from dectin-1 KO mice suggest that beta-glucan-dependent modulation of fungal immunity and host resistance is rather a multilayered process that is constantly shaped by a panoply of factors including fungal strain and species, genetic background of mice, specific immune cell population, fungal load, ligand type and purity, etc.

3. Alternative Receptors

3.1. CR3 KO Mice

Several alternative receptors for beta-glucans have also been described in literatures (Figure 3). Complement receptor 3 (CR3), a heterodimer comprising of αM and β2 subunits, is part of the integrin family of adhesion molecules that has been widely accepted as the principal receptor for beta-glucans long before dectin-1 discovery [113,114]. Examination of phagocytic neutrophils from CR3-deficient mice (syn. αMβ2−/−, CD11b−/−, CD18−/−, Mac-1−/−, Itgam−/−, Itgb2−/−) has unveiled the requisite role of this receptor in opsonic and non-opsonic recognition and phagocytosis of both particulate and soluble beta-glucans (Table 1). As illuminated in the study of Xia and colleagues [115] and in conformity with early human studies [113,116], the phagocytic ability of neutrophils was prominently reduced (~60%) upon exposure to serum-opsonized zymosan, whereas uptake of particulate beta-glucans was entirely abrogated in CR3 KO mice as opposed to control mice. Conflicting data exist, meanwhile, when considering other phagocytes such as macrophages, DC, and NK cells. This may occur within species where dependence for CR3 was debated to be involved in the phagocytosis of particulate beta-glucans in mice [115,117] or may arise interspecies-specifically where macrophage ingestion of unopsonized yeast particles was suggested to necessitate the recognition by CR3 receptors in humans [118,119] but not in mice [33].
Emerging evidence from human studies and CR3-deficient mice has designated a distinct niche for this particular PRR in beta-glucan research. Firstly, neutrophil-mediated anti-fungal immunity is predominantly dictated by CR3. Following induction of disseminated histoplasmosis, CR3 (Itgam)-deficient mice revealed a remarkable decrease in splenic levels of TNF-α, IL-17 and IFN-γ cytokines accompanied by a significant reduction of CD4+ and CD8+ T cells, increased proliferation of H. capsulatum and diminished SYK-JNK-AP1 signal transduction [62]. Concordantly, Techner and co-workers [120] underlined the significant depression of pro-inflammatory cytokines, enhanced fungal burden, and depressed bronchial inflammation in A. fumigatus-infected CR3(CD11b) KO mice. On the other hand, Li et al. [121] and another group [68] speculated that repression of CR3 substantially inhibits engulfment of C. albicans due to a faulty LC3B-II autophagosome accumulation in human neutrophils or due to impaired RhoGTPases exchange factors (vav1 and vav3) in neutrophils of CR3(Mac-1/CD11b) KO mice, respectively. Secondly, CR3 receptors may execute the killing of fungal hyphae or filamentous forms. In comparison to the ineffective action of dectin-1 and TLR2 against fungal hyphae [92], deletion of CR3 in CD18 KO mice neutrophils caused an impaired elimination of A. fumigatus and C. albicans hyphae coupled with a defect in calprotectin release and neutrophil extracellular trap (NET) formation [72]. Therefore, CR3 represents a promising beta-glucan receptor in neutrophils that may be exploited for anti-fungal activity.

3.2. EphA2 KO Mice

Just a couple of years ago, a novel PRR for beta-glucans that belongs to the receptor tyrosine kinase (RTK) superfamily had been introduced—the ephrin type-A receptor 2 (EphA2) [73,122] (Figure 3). EphA2 has been known to be involved in various physiological functions such as cell–cell communication, cell growth and differentiation, and cell migration [123,124], as well as in prostate, mammary, esophageal, cervical, lung, ovarian, renal cancers and leukemia [125,126,127,128,129,130,131,132], and inflammatory conditions such as ischemia-reperfusion, psoriasis, atherosclerosis, and acute lung injury [133,134]. In the recent breakthrough study by Swidergall et al. [73], it has been characterized as an epithelial-type of PRR in the oral epithelium that fulfills an incredulous function in host defense against oropharyngeal candidiasis (OPC) (Table 1). C. albicans-infected EphA2-deficient mice disclosed significantly undermined early anti-fungal responses, with decreased levels of various chemokines such as CCL3 and CXCL1/KC, and cytokines like IL-1β, IFN-γ, and IL-17A. An inquiry into the underlying mechanism incriminates the stringent control exerted by EphA2 signaling on two signal transduction pathways, the mitogen associated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3), both of which are considered critical in oral mucosal fungal sensing and immunity [135,136].
EphA2 has also been known to play diverse roles in anti-fungal immunity. Its relevance in oral fungal resistance has been exemplified by the sharp reduction in the frequency of recruited neutrophils and inflammatory monocytes in EphA2 KO mice relative to WT animals [137]. Succeeding experiments showed that EphA2 in neutrophils but not in inflammatory monocytes is vital in conferring resistance against serum-opsonized C. albicans yeast during the restricted early period of infection. Following contact of EphA2 receptors to serum-opsonized yeast, the p40phox cytosolic protein of the NADPH oxidase system is concomitantly phosphorylated, eventually stimulating ROS-mediated fungal killing activity [137]. Similar to what has been described in dectin-1 receptors, EphA2 does not participate in the clearance of invasive fungal hyphae, but binds with other fungal species (C. glabrata, A. fumigatus, Rhizopus delemar), and collaborates with other PRR, specifically the epidermal growth factor receptor (EGFR), which governs the uptake of pervading fungal pathogens and sustains EphA2 signaling by stabilizing receptor phosphorylation [73,138]. Collectively, this series of information, together with the limited contribution of classical beta-glucan PRRs in addressing oropharyngeal infection [139], indicate the compelling role of EphA2 in holding the fort in oral mucosal immunity.
Other known receptors for beta-glucans include lactosylceramide (LacCer) [140]. Currently, information is scarce regarding its precise role in beta-glucan function and signaling.

4. Closing Remarks

The utility of various beta-glucan receptor deficient mouse models during the last couple of decades has shed important light and answered mystifying conundrums concerning the composite roles of beta-glucans in various physiological processes and diseases. Although the bulk of published data have been concentrated on its role in fungal immunity, there are still unknown aspects to be learnt and decoded in this area. As new insights have gradually becoming available, especially on previously unexplored and understudied facets of beta glucan research, and as novel beta-glucan receptors are continually being elucidated, these receptor-deficient animals will stay relevant in the coming years and command more enthusiasm especially from scientists and researchers who are advancing the field of translational medicine.

Author Contributions

Conceptualization, S.K; writing—original draft preparation, M.J.M.D. and S.K.; writing—review and editing, M.J.M.D., S.K., and S.-H.C. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Acknowledgments

This study was supported by KAKENHI, Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area) [grant #23114504] (S.K.).

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

BMDCbone marrow-derived dendritic cells
BMDMbone marrow-derived macrophages
CaMKcalmodulin-dependent kinase II
CARDcaspase recruitment domain family member 9
CBMCARD9-BCL10-MALT1
CLECC-type lectin receptor
CRDcarbohydrate recognition domain
CREBcAMP-response element-binding protein
CR3complement receptor 3
DCdendritic cells
DCIRdendritic cell immunoreceptor
DSSdextran sulfate sodium
EphA2ephrin type-A receptor 2
ITAMimmunoreceptor tyrosine-based activation motif
LacCerlactosylceramide
MALT1mucosa-associated lymphoid tissue 1
MAPKmitogen-associated protein kinase
NaClOsodium hypochlorite
NKnatural killer
OPCoropharyngeal candidiasis
PAMPpathogen associated molecular pattern
PRRpathogen recognition receptor
PYK2proline-rich tyrosine kinase II
ROSreactive oxygen species
RTKreceptor tyrosine kinase
SH2SRC homology 2
SNPsingle nucleotide polymorphism
SPGSparassis crispa glucan
STAT3signal transducer and activator of transcription 3
TLRtoll-like receptor

References

  1. Vetvicka, V.; Vetvicka, J. Glucan supplementation enhances the immune response againstan influenza challenge in mice. Ann. Transl. Med. 2015, 3, 22. [Google Scholar] [PubMed]
  2. Kuda, T.; Kosaka, M.; Hirano, S.; Kawahara, M.; Sato, M.; Kaneshima, T.; Nishizawa, M.; Takahashi, H.; Kimura, B. Effect of sodium-alginate and laminaran on Salmonella typhimurium infection in human enterocyte-like HT-29-Luc cells and balb/c mice. Carbohydr. Polym. 2015, 125, 113–119. [Google Scholar] [CrossRef]
  3. Bobek, P.; Galbavy, S. Effect of pleuran (β-glucan from Pleurotus ostreatus) on the antioxidant status of the organism and on dimethylhydrazine-induced precancerous lesions in rat colon. Br. J. Biomed. Sci. 2001, 58, 164–168. [Google Scholar]
  4. Shen, R.-L.; Wang, Z.; Dong, J.-L.; Xiang, Q.-S.; Liu, Y.-Q. Effects of oat soluble and insoluble β-glucan on 1,2-dimethylhydrazine-induced early colon carcinogenesis in mice. Food Agric. Immunol. 2016, 27, 657–666. [Google Scholar] [CrossRef] [Green Version]
  5. Desamero, M.J.; Kakuta, S.; Chambers, J.K.; Uchida, K.; Hachimura, S.; Takamoto, M.; Nakayama, J.; Nakayama, H.; Kyuwa, S. Orally administered brown seaweed-derived β-glucan effectively restrained development of gastric dysplasia in A4gnt KO mice that spontaneously develop gastric adenocarcinoma. Int. Immunopharmacol. 2018, 60, 211–220. [Google Scholar] [CrossRef] [PubMed]
  6. Ruthes, A.C.; Carbonero, E.R.; Cordova, M.M.; Baggio, C.H.; Santos, A.R.S.; Sassaki, G.L.; Cipriani, T.R.; Gorin, P.A.J.; Lacomini, M. Lactarius rufus (1->3), (1->6)-β-D-glucans: Structure, antinociceptive and anti-inflammatory effects. Carbohydr. Polym. 2013, 94, 1236–1291. [Google Scholar] [CrossRef] [Green Version]
  7. Silveira, M.L.L.; Smiderle, F.R.; Moraes, C.P.; Borato, D.G.; Baggio, C.H.; Ruthers, A.R.; Wisbeck, E.; Sassaki, G.L.; Cipriani, T.R.; Furlan, S.A.; et al. Structural characterization and anti-inflammatory activity of linear β-D-glucan isolated from Pleurotus sajor-caju. Carbohydr. Polym. 2014, 113, 588–596. [Google Scholar] [CrossRef]
  8. Snart, J.; Bibiloni, R.; Grayson, T.; Lay, C.; Zhang, H.; Allison, G.E.; Laverdiere, J.K.; Temelli, F.; Vasanthan, T.; Bell, R.; et al. Supplementation of the diet with high-viscosity beta-glucan results in enrichment for Lactobacilli in the rat cecum. Appl. Environ. Microbiol. 2006, 72, 1925–1931. [Google Scholar] [CrossRef] [Green Version]
  9. Kofuji, K.; Aoki, A.; Tsubaki, K.; Konishi, M.; Isobe, T.; Murata, Y. Antioxidant activity of β-glucan. ISRN Pharm. 2012, 2012, 125864. [Google Scholar]
  10. Sener, G.; Eksioglu-Demiralp, E.; Cetiner, M.; Ercan, F.; Yegen, B.C. β-glucan ameliorates methotrexate-induced oxidative organ injury via its antioxidant and immunomodulatory effects. Eur. J. Pharmacol. 2006, 542, 170–178. [Google Scholar] [CrossRef]
  11. Yamanaka, D.; Tada, R.; Adachi, Y.; Ishibashi, K.-I.; Motoi, M.; Iwakura, Y.; Ohno, N. Agarius brasiliensis-derived β-glucans exert immunoenhaning effects via a dectin-1 –dependent pathway. Int. Immunopharmacol. 2012, 14, 311–319. [Google Scholar] [CrossRef]
  12. Jenkins, A.L.; Jenkins, D.J.A.; Zdravkovic, U.; Wursch, P.; Vuksan, V. Depression of the glycemic index by high levels β-glucan fiber in two functional foods tested in type 3 diabetes. Eur. J. Clin. Nutr. 2002, 56, 622–628. [Google Scholar] [CrossRef] [PubMed]
  13. Novak, M.; Vetvicka, V. β-glucans, history, and the present: Immunomodulatory aspects and mechanisms of action. J. Immunotoxicol. 2008, 5, 47–57. [Google Scholar] [CrossRef]
  14. Silva, V.O.; Moura, N.O.; de Oliveira, L.J.R.; Peconick, A.P.; Pereira, L.J. Promising effects of beta-glucans in metabolism and on the immune responses: Review article. Am. J. Immunol. 2017, 13, 62–72. [Google Scholar] [CrossRef]
  15. Samuelsen, A.B.C.; Schrezenmeir, J.; Knutsen, S.H. Effects of orally administered yeast-derived beta-glucans: A review. Mol. Nutr. Food Res. 2014, 58, 183–193. [Google Scholar] [CrossRef] [PubMed]
  16. Steimbach, L.; Borgmann, A.V.; Gomar, G.G.; Hoffmann, L.V.; Rutckeviski, R.; de Andrade, D.P.; Smiderle, F.R. Fungal beta-glucans as adjuvants for treating cancer patients- A systematic review of clinical trials. Clin. Nutr. 2020, S0261–S5614, 30650–30656. [Google Scholar]
  17. Figdor, C.G.; van Kooyk, Y.; Adema, G.J. C-type lectin receptors on dendritic cells and langerhan cells. Nat. Rev. Immunol. 2002, 2, 77–84. [Google Scholar] [CrossRef]
  18. Brown, G.D.; Gordon, S. Fungal β-glucans and mammalian immunity. Immunity 2003, 19, 311–315. [Google Scholar] [CrossRef] [Green Version]
  19. Roger, N.C.; Slack, E.C.; Edwards, A.D.; Nolte, M.A.; Schulz, O.; Schweighoffer, E.; Wiliams, D.L.; Gordon, S.; Tybulewicz, V.L.; Brown, G.D.; et al. Syk-dependent cytokine induction by decti-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 2005, 22, 507. [Google Scholar] [CrossRef] [Green Version]
  20. Mambula, S.S.; Sau, K.; Henneke, P.; Golenbock, D.T.; Levitz, S.M. Toll-like receptor (tlr) signaling in response to Aspergillus fumigatus. J. Biol. Chem. 2002, 277, 39320–39326. [Google Scholar] [CrossRef] [Green Version]
  21. Capecchi, M.R. Gene targeting in mice: Functional analysis of the mammalian genome for the twenty-first century. Nat. Rev. Genet. 2005, 6, 507–512. [Google Scholar] [CrossRef]
  22. Brown, G.D.; Gordon, S. Immune recognition. A new receptor for beta-glucans. Nature 2001, 413, 36. [Google Scholar] [CrossRef] [PubMed]
  23. Brown, G.D.; Herre, J.; Williams, D.L.; Willment, J.A.; Marshall, A.S.; Gordon, S. Dectin-1 mediates the biological effects of beta-glucans. J. Exp. Med. 2003, 197, 1119–1124. [Google Scholar]
  24. Taylor, P.R.; Tsoni, S.V.; Willment, J.A.; Dennehy, K.M.; Rosas, M.; Findon, H.; Haynes, K.; Steele, C.; Botto, M.; Gordon, S.; et al. Dectin-1 is required for beta-glucan recognition and control of fungal infection. Nat. Immunol. 2007, 8, 31–38. [Google Scholar] [CrossRef]
  25. Saijo, S.; Fujikado, N.; Furuta, T.; Chung, S.-H.; Kotaki, H.; Seki, K.; Sudo, K.; Akira, A.; Adachi, Y.; Ohno, N.; et al. Dectin-1 is required for host defense against Pneumocystis carinii but not against Candida albicans. Nat. Immunol. 2007, 8, 39–46. [Google Scholar] [CrossRef] [PubMed]
  26. Brown, G.D.; Taylor, P.R.; Reid, D.M.; Willment, J.A.; Williamns, D.L.; Martinez-Pomares, L.; Wong, S.Y.C.; Gordon, S. Dectin-1 is a major β-glucan receptor on macrophages. J. Exp. Med. 2002, 196, 407–412. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Ariizumi, K.; Shen, G.L.; Shikano, S.; Xu, S.; Ritter, R., 3rd; Kumamoto, T.; Edelbaum, D.; Morita, A.; Bergstresser, P.R.; Takashima, A. Identification of a novel, dendritic cell-associated molecule, dectin-1, by substractive cDNA cloning. J. Biol. Chem. 2000, 275, 20157–20167. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Saijo, S.; Iwakura, Y. Dectin-1 and dectin-2 in innate immunity against fungi. Int. Immunol. 2011, 23, 467–472. [Google Scholar] [CrossRef]
  29. Spiess, M. The asialoglycoprotein receptor: A model for endocytic transport receptors. Biochemistry 1990, 29, 10009–10018. [Google Scholar] [CrossRef]
  30. Yokota, K.; Takashima, A.; Bergstresser, P.R.; Ariizumi, K. Identification of a human homologue of the dendritic cell-associated C-type lectin, dectin-1. Gene 2001, 272, 51–60. [Google Scholar] [CrossRef]
  31. Ariizumi, K.; Shen, G.-L.; Shikano, S.; Ritter, R., III; Zukas, P.; Edelbaum, D.; Morita, A.; Takashima, A. Cloning of a second dendritic-cell associated c-type lectin (dectin-2) and its alternatively spliced isoforms. J. Biol. Chem. 2000, 275, 11957–11963. [Google Scholar] [CrossRef] [Green Version]
  32. Willment, J.A.; Gordon, S.; Brown, G.D. Characterization of the human β-glucan receptor and its alternatively spliced isoforms. J. Biol. Chem. 2001, 276, 43818–43823. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Gantner, B.N.; Simmons, R.M.; Canavera, S.J.; Akira, S.; Underhill, D.M. Collaborative induction of inflammatory responses by dectin-1 and toll-like receptor 2. J. Exp. Med. 2003, 197, 1107–1117. [Google Scholar] [CrossRef] [Green Version]
  34. Taylor, P.R.; Brown, G.D.; Reid, D.M.; Willment, J.A.; Martinez-Pomares, L.; Gordon, S.; Wong, S.Y.C. The β-glucan receptor, dectin-1, is predominantly expressed on the surface of cells of the monocyte/macrophage and neutrophil lineages. J. Immunol. 2002, 169, 3876–3882. [Google Scholar] [CrossRef] [Green Version]
  35. Cohen-Kedar, S.; Baram, L.; Elad, H.; Brazowski, E.; Guzner-Gur, H.; Dotan, I. Human intestinal epithelial cells respond to β-glucans via dectin-1 and syk. Eur. J. Immunol. 2014, 44, 3729–3740. [Google Scholar] [CrossRef]
  36. Volman, J.L.; Mensink, R.P.; Buurman, W.A.; Onning, G.; Plat, J. The absence of functional dectin-1 on enterocytes may serve to prevent intestinal damage. Eur. J. Gastroenterol. Hepatol. 2020, 22, 88–94. [Google Scholar] [CrossRef]
  37. Czop, J.K.; Fearon, D.T.; Austen, K.F. Opsonin-independent phagocytosis of activators of the alternative complement pathway by human monocytes. J. Immunol. 1978, 120, 1132–1138. [Google Scholar]
  38. Gantner, B.N.; Simmons, R.M.; Underhill, D.M. Dectin-1 mediates macrophage recognition of Candida albicans yeast but not filaments. EMBO J. 2005, 24, 1277–1286. [Google Scholar] [CrossRef] [Green Version]
  39. Netea, M.G.; Brown, G.D.; Kullberg, B.J.; Gow, N.A. An integrated model of the recognition of Candida albicans by the innate immune system. Nat. Rev. Microbiol. 2008, 6, 67. [Google Scholar] [CrossRef]
  40. Hara, H.; Ishihara, C.; Takeuchi, A.; Imanishi, T.; Xue, L.; Morris, S.W.; Inui, M.; Takai, T.; Shibuya, A.; Saijo, S. The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and toll-like receptors. Nat. Immunol. 2007, 8, 619. [Google Scholar] [CrossRef]
  41. Mocsai, A.; Ruland, J.; Tybulewicz, V.L.J. The SYK tyrosine kinase: A crucial player in diverse biological functions. Nat. Rev. Microbiol. 2010, 10, 387–402. [Google Scholar] [CrossRef]
  42. Underhill, D.M.; Rossnagle, E.; Lowell, C.A.; Simmons, R.M. Dectin-1 activates Syk tyrosine kinase in a dynamic subset of macrophages for reactive oxygen production. Blood 2005, 106, 2543–2550. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Herre, J.; Marshall, A.S.J.; Caron, E.; Edwards, A.D.; Williams, D.L.; Schweighoffer, E.; Tybulewicz, V.; Sousa, C.R.; Gordon, S.; Brown, G.D. Dectin-1 uses novel mechanisms for yeast phagocytosis in macrophages. Blood 2004, 104, 4038–4045. [Google Scholar] [CrossRef] [Green Version]
  44. Bertin, J.; Guo, Y.; Wang, L.; Srinivasula, S.M.; Jacobson, M.D.; Poyet, J.-L.; Merriam, S.; Du, M.-Q.; Dyer, M.J.S.; Robinson, K.E.; et al. CARD9 is a novel caspase recruitment domain-containing protein that interacts with BCL10/CLAP and activates NF-kappa B. J. Biol. Chem. 2000, 275, 41082. [Google Scholar] [CrossRef] [Green Version]
  45. Gross, O.; Gewies, A.; Finger, K.; Schafer, M.; Sparwasser, T.; Peschel, C.; Forster, I.; Ruland, J. CARD9 controls a non-TLR signaling pathway for innate anti-fungal immunity. Nature 2006, 442, 651. [Google Scholar] [CrossRef] [PubMed]
  46. LeibundGut-Landmann, S.; Gross, O.; Robinson, M.J.; Osorio, F.; Slack, E.C.; Tsoni, S.V.; Schweighoffer, E.; Tybulewicz, V.; Brown, G.D.; Ruland, J.; et al. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat. Immunol. 2007, 8, 630–638. [Google Scholar] [CrossRef]
  47. Gringhuis, S.I.; den Dunnen, J.; Litjens, M.; van der Vlist, M.; Wevers, B.; Bruijns, S.C.M.; Geijtenbeek, T.B.H. Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-kappaB activation through Raf-1 and Syk. Nat. Immunol. 2009, 10, 203. [Google Scholar] [CrossRef]
  48. Drummond, R.A.; Saijo, S.; Iwakura, Y.; Brown, G.D. The role of Syk/CARD9 coupled C-type lectins in antifungal immunity. Eur. J. Immunol. 2011, 41, 276. [Google Scholar] [CrossRef]
  49. Dennehy, K.M.; Willment, J.A.; Williams, D.L.; Brown, G.D. Reciprocal regulation of IL-23 and IL-12 following co-activation of dectin-1 and TLR signaling pathways. Eur. J. Immunol. 2009, 39, 1379–1386. [Google Scholar] [CrossRef]
  50. Kelly, E.K.; Wang, L.; Ivashkiv, L.B. Calcium-activated pathways and oxidative burst mediate zymosan-induced signaling and IL-10 production in human macrophages. J. Immunol. 2010, 184, 5545–5552. [Google Scholar] [CrossRef]
  51. Tam, J.M.; Reedy, J.L.; Lukason, D.P.; Kuna, S.G.; Acharya, M.; Khan, N.S.; Negoro, P.E.; Xu, S.; Ward, R.A.; Feldman, M.B.; et al. Tetraspanin CD82 organizes dectin-1 into signaling domains to mediate cellular responses to Candida albicans. J. Immunol. 2019, 202, 3256–3266. [Google Scholar] [CrossRef]
  52. Mattiola, I.; Tomay, F.; De Pizzol, M.; Silva-Gomes, R.; Savino, B.; Gulic, T.; Doni, A.; Lonardi, S.; Boutet, M.A.; Nerviani, A.; et al. The macrophage tetraspananMS4A4A enhances dectin-1-dependent NK cell-mediated resistance to metastasis. Nat. Immunol. 2019, 20, 1012–1022. [Google Scholar] [CrossRef]
  53. Nakamura, K.; Kinjo, T.; Saijo, S.; Miyamoto, A.; Adachi, Y.; Ohno, N.; Fujita, J.; Kaku, M.; Iwakura, Y.; Kawakami, K. Dectin-1 is not required for the host defense to Cryptococcus neoformans. Microbiol. Immunol. 2007, 51, 1115–1119. [Google Scholar] [CrossRef]
  54. Werner, J.L.; Metz, A.E.; Horn, D.; Schoeb, T.R.; Hewitt, M.M.; Schwiebert, L.M.; Faro-Trindade, I.; Brown, G.D.; Steele, C. Requisite role for dectin-1 beta-glucan receptor in pulmonary defense against Aspergillus fumigatus. J. Immunol. 2009, 182, 4938. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Galès, A.; Conduché, A.; Bernad, J.; Lefevre, L.; Olagnier, D.; Béraud, M.; Martin-Blondel, G.; Linas, M.D.; Auwerx, J.; Coste, A.; et al. PPARγ controls Dectin-1 expression required for host antifungal defense against Candida albicans. PLoS Pathog. 2010, 6, e1000714. [Google Scholar] [CrossRef] [Green Version]
  56. Rivera, A.; Hohl, T.M.; Collins, N.; Leiner, I.; Gallegos, A.; Saijo, S.; Coward, J.W.; Iwakura, Y.; Pamer, E.G. Dectin-1 diversifies Aspergillus fumigatus-specific T cell responses by inhibiting T helper type 1 CD4 T cell differentiation. J. Exp. Med. 2011, 208, 369–381. [Google Scholar] [CrossRef]
  57. Bhatia, S.; Fei, M.; Yarlagadda, M.; Qi, Z.; Akira, S.; Saijo, S.; Iwakura, Y.; van Rooijen, N.; Gibson, G.A.; St Croix, C.M.; et al. Rapid host defense against Aspergillus fumigatus involves alveolar macrophages with a predominance of alternatively activated phenotype. PLoS ONE 2011, 6, e15943. [Google Scholar] [CrossRef] [Green Version]
  58. Iliev, I.D.; Funari, V.A.; Taylor, K.D.; Nguyen, Q.; Reyes, C.N.; Strom, S.P.; Brown, J.; Becker, C.A.; Fleshner, P.R.; Dubinsky, M.; et al. Interaction between commensal fungi and the C-type lectin receptor dectin-1 influence colitis. Science 2012, 336, 1314–1317. [Google Scholar] [CrossRef] [Green Version]
  59. Viriyakosol, S.; Jimenez, M.D.P.; Gurney, M.A.; Ashbaugh, M.E.; Fierer, J. Dectin-1 is required for resistance to coccidioidomycosis in mice. MBio 2013, 4, e00597-12. [Google Scholar] [CrossRef] [Green Version]
  60. Loures, F.V.; Araújo, E.F.; Feriotti, C.; Bazan, S.; Costa, T.A.; Brown, G.D.; Calich, V.L. Dectin-1 induces M1 macrophages and prominent expansion of CD8+IL-17+ cells in pulmonary Paracoccidioidomycosis. J. Infect. Dis. 2014, 210, 762–773. [Google Scholar] [CrossRef] [Green Version]
  61. Tang, C.E.; Kamiya, T.; Liu, Y.; Kadoki, M.; Kakuta, S.; Oshima, K.; Hattori, M.; Takeshita, K.; Kanai, T.; Saijo, S.; et al. Inhibition of dectin-1 signaling ameliorates colitis by inducing Lactobaccilus-mediated regulatory T cell expansion in the intestine. Cell Host Microbe 2015, 18, 183–197. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Huang, J.-H.; Lin, C.-Y.; Wu, -Y.; Chen, W.-Y.; Chu, C.-L.; Brown, G.D.; Chuu, C.-P.; Wu-Hsieh, B.A. CR3 and dectin-1 collaborate in macrophage cytokine response through association on lipid rafts and activation of Syk-JNK-AP-1 pathway. PLoS Pathog. 2015, 11, e1004985. [Google Scholar] [CrossRef] [Green Version]
  63. Higashino-Kameda, M.; Yabe-Wada, T.; Matsuba, S.; Takeda, K.; Anzawa, K.; Mochizuki, T.; Makimura, K.; Saijo, S.; Iwakura, Y.; Toga, H.; et al. A critical role of Dectin-1 in hypersensitivity pneumonitis. Inflamm. Res. 2016, 65, 235–244. [Google Scholar] [CrossRef]
  64. Yoshikawa, F.S.Y.; Yabe, R.; Iwakura, Y.; de Almeida, S.R.; Saijo, S. Dectin-1 and dectin-2 promote control of the fungal pathogen Trichophyton rubrum independently of IL-17 and adaptive immunity in experimental deep dermatophytosis. Innate Immun. 2016, 22, 316–324. [Google Scholar] [CrossRef] [PubMed]
  65. Wuthrich, M.; Gern, B.; Hung, C.Y.; Ersland, K.; Rocco, N.; Pick-Jacobs, J.; Galles, K.; Filutowicz, H.; Warner, T.; Evans, M.; et al. Vaccine-induced protection against 3 systemic mycoses endemic to North America requires Th17 cells in mice. J. Clin. Investig. 2011, 121, 554–568. [Google Scholar] [CrossRef] [PubMed]
  66. Chen, S.M.; Zou, Z.; Qiu, X.R.; Hou, W.T.; Zhang, Y.; Fang, W.; Chen, Y.L.; Wang, Y.D.; Jiang, Y.Y.; Shen, H.; et al. The critical role of Dectin-1 in host controlling systemic Candida krusei infection. Am. J. Transl. Res. 2019, 11, 721–732. [Google Scholar]
  67. Brandhorst, T.T.; Wüthrich, M.; Finkel-Jimenez, B.; Warner, T.; Klein, B.S. Exploiting type 3 complement receptor for TNF-α suppression, immune evasion, and progressive pulmonary fungal infection. J. Immunol. 2004, 173, 7444–7453. [Google Scholar] [CrossRef] [Green Version]
  68. Li, X.; Utomo, A.; Cullere, X.; Choi, M.M.; Milner, D.A., Jr.; Venkatesh, D.; Yun, S.-H.; Mayadas, T.N. The β-glucan receptor dectin-1 activates the integrin Mac-1 in neutrophils via Vav protein signaling to promote Candida albicans clearance. Cell Host Microbe 2011, 10, 603–615. [Google Scholar] [CrossRef] [Green Version]
  69. Soloviev, D.A.; Jawhara, S.; Fonzi, W.A. Regulation of innate immune response to Candida albicans infections by αMβ2-Pra1p interaction. Infect. Immun. 2011, 79, 1546–1558. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  70. Leal, S.M., Jr.; Vareechon, C.; Cowden, S.; Cobb, B.A.; Latgé, J.P.; Momany, M.; Pearlman, E. Fungal antioxidant pathways promote survival against neutrophils during infection. J. Clin. Investig. 2012, 122, 2482–2498. [Google Scholar] [CrossRef] [Green Version]
  71. Sun, D.; Sun, P.; Li, H.; Zhang, M.; Liu, G.; Strickland, A.B.; Chen, Y.; Fu, Y.; Xu, J.; Yosri, M.; et al. Fungal dissemination is limited by liver macrophage filtration of the blood. Nat. Commun. 2019, 10, 4566. [Google Scholar] [CrossRef]
  72. Clark, H.L.; Abbondante, S.; Minns, M.S.; Greenberg, E.N.; Sun, Y.; Pearlman, E. Protein deiminase 4 and CR3 regulate Aspergillus fumigatusi and β-glucan-induced neutrophil extracellular trap formation, but hyphal killing is I dependent only in CR3. Front. Immunol. 2018, 9, 1182. [Google Scholar] [CrossRef] [PubMed]
  73. Swidergall, M.; Solis, N.V.; Lionakis, M.S.; Filler, S.G. EphA2 is an epithelial cell pattern recognition receptor for fungal β-glucans. Nat. Microbiol. 2018, 3, 53–61. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Esteban, A.; Popp, M.W.; Vyas, V.K.; Strijbis, K.; Ploegh, H.L.; Fink, G.R. Fungal recognition is mediated by the association of dectin-1 and galectin-3 in macrophages. Proc. Natl. Acad. Sci. USA 2011, 108, 14270–14275. [Google Scholar] [CrossRef] [Green Version]
  75. Plantinga, T.S.; van der Velden, W.J.F.M.; Ferwerda, B.; van Spriel, A.B.; Adema, G.; Feuth, T.; Donnelly, J.P.; Brown, G.D.; Kullberg, B.-J.; Blijlevens, N.M.A.; et al. Early stop polymorphism in human DECTIN-1 is associated with increased candida colonization in hematopoietic stem cell transplant recipients. Clin. Infect. Dis. 2009, 49, 724. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. van der Velden, W.J.; Plantinga, T.S.; Feuth, T.; Donnelly, J.P.; Netea, M.G.; Blijlevens, N.M. The incidence of acute graft-versus-host increases with Candida colonization depending the dectin-1 gene status. Clin. Immunol. 2010, 136, 302. [Google Scholar] [CrossRef] [PubMed]
  77. Drummond, R.A.; Dambuza, I.M.; Vautier, S.; Taylor, J.A.; Reid, D.M.; Bain, C.C.; Underhill, D.M.; Masopust, D.; Kaplan, D.H.; Brown, G.D. CD4+ t-cell survival in the GI tract requires dectin-1 during fungal infection. Mucosal Immunol. 2016, 9, 492–502. [Google Scholar] [CrossRef]
  78. Hise, A.G.; Tomalka, J.; Ganesan, S.; Patel, K.; Hall, B.A.; Brown, G.D.; Fitzgerald, K.A. An essential role for the NLRP3 inflammasome in host defense against the human pathogen, Candida albicans. Cell Host Microbe 2009, 5, 487–497. [Google Scholar] [CrossRef] [Green Version]
  79. Vautier, S.; Drummond, R.A.; Redelinghuys, P.; Murray, G.I.; MacCallum, D.M.; Brown, G.D. Dectin-1 is not required for controlling Candida albicans colonization of the gastrointestinal tract. Infect. Immun. 2012, 80, 4216–4222. [Google Scholar] [CrossRef] [Green Version]
  80. Marakalala, M.J.; Vautier, S.; Potrykus, J.; Walker, L.A.; Shepardson, K.M.; Hopke, A.; Mora-Montes, H.M.; Kerrigan, A.; Netea, M.G.; Murray, G.I.; et al. Differential adaptation of Candida albicans in vivo modulates immune recognition by dectin-1. PLoS Pathog. 2013, 9, e1003315. [Google Scholar] [CrossRef]
  81. Rappleye, C.A.; Eissenberg, L.G.; Goldman, W.E. Histoplasma capsulatum alpha-(1,3) glucan blocks innate immune recognition by the beta-glucan receptor. Proc. Natl. Acad. Sci. USA 2007, 104, 1366–1370. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Carvalho, A.; Giovannini, G.; De Luca, A.; D’Angelo, C.; Casagrande, A.; Iannitti, R.G.; Ricci, G.; Cunha, C.; Romani, L. Dectin-1 isoforms contribute to distinct Th1/Th17 cell activation in mucosal candidiasis. Cell. Mol. Immunol. 2012, 9, 276–286. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Del Pilar Jimenez-A, M.; Viriyakosol, S.; Walls, L.; Datta, S.K.; Kirkland, T.; Heinsbroek, S.E.M. Susceptibility to Coccidioides species in C57BL/6 mice is associated with expression of a truncated splice variant of dectin-1 (Clec7a). Genes Immun. 2008, 9, 338–348. [Google Scholar] [CrossRef] [Green Version]
  84. Kirkland, T.N.; Fierer, J. Inbred mouse strains differ in resistance to lethal Coccidiodes immitis infection. Infect. Immun. 1983, 40, 912–916. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Heinsbroek, S.E.M.; Taylor, P.R.; Rosas, M.; Wilment, J.A.; Williams, D.L.; Gordon, S.; Brown, G.D. Expression of functionally different dectin-1 isoforms by murine macrophages. J. Immunol. 2006, 176, 5513–5518. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Fischer, M.; Muller, J.P.; Spies-Weisshart, B.; Grafe, C.; Kurzai, O.; Hunniger, K.; Hochhaus, A.; Scholl, S.; Schnetzke, U. Isoform localization of dectin-1 regulates the signaling quality of anti-fungal immunity. Eur. J. Immunol. 2017, 47, 848–859. [Google Scholar] [CrossRef]
  87. Ashman, R.; Fulurija, A.; Papadimitrou, J.M. Strain-dependent difference in host response to Candida albicans infection in mice are related to organ susceptibility and infectious load. Infect. Immun. 1996, 64, 1866–1869. [Google Scholar] [CrossRef] [Green Version]
  88. Steele, C.; Rapaka, R.R.; Metz, A.; Pop, S.M.; Williams, D.L.; Gordon, S.; Kolls, J.K.; Brown, G.D. The beta-glucan receptor dectin-1 recognizes specific morphologies of Aspergillus fumigatus. PLoS Pathog. 2005, 1, e42. [Google Scholar] [CrossRef] [Green Version]
  89. Hohl, T.M.; Van Epps, H.L.; Rivera, A.; Morgan, L.A.; Chen, P.L.; Feldmesser, M.; Pamer, E.G. Aspergillus fumigatus triggers inflammatory responses by stage-specific β-glucan display. PLoS Pathog. 2005, 1, e30. [Google Scholar] [CrossRef] [Green Version]
  90. Lewis, L.E.; Bain, J.M.; Lowes, C.; Gillespie, C.; Rudkin, F.M.; Gow, N.A.R.; Erwig, L.-P. Stage specific assessment of Candida albicans phagocytosis by macrophages identifies cell wall composition and morphogenesis as key determinants. PLoS Pathog. 2012, 8, e1002578. [Google Scholar] [CrossRef] [Green Version]
  91. Wheeler, R.T.; Fink, G.R. A drug-sensitive genetic network masks fungi from the immune system. PLoS Pathog. 2006, 2, e35. [Google Scholar] [CrossRef]
  92. Gow, N.A.R.; Netea, M.G.; Munro, C.A.; Ferwerda, G.; Bates, S.; Mora-Montes, H.M.; Walker, L.; Jansen, T.; Jacobs, L.; Tsoni, V.; et al. Immune recognition of Candida albicans β-glucan by dectin-1. J. Infect. Dis. 2007, 196, 1565–1671. [Google Scholar] [CrossRef] [Green Version]
  93. Klis, F.M.; de Groot, P.; Hellingwerf, K. Molecular organization of the cell wall of Candida albicans. Med. Mycol. 2001, 39, 1–8. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Borges-Walmsley, M.E.; Chen, D.; Shu, X.; Walmsley, A.R. The pathobiology of Paracococcidioides brasiliensis. Trends Microbiol. 2002, 10, 80–87. [Google Scholar] [CrossRef]
  95. Kozel, T.R. Virulence factors of Cryptococcus neoformans. Trends Microbiol. 1995, 3, 295–299. [Google Scholar] [CrossRef]
  96. Miura, N.M.; Miura, T.; Ohno, N.; Adachi, Y.; Watanabe, M.; Tamura, H.; Tanaka, S.; Yadomae, T. Gradual solubilization of Candida cell wall β-glucan by oxidative degradation in mice. FEMS Immunol. Med. Microbiol. 1998, 21, 123–129. [Google Scholar] [CrossRef]
  97. Suzuki, T.; Ohno, N.; Oshima, Y.; Yadomae, T. Soluble mannan and beta-glucan inhibit the uptake of Malassezia furfur by human monocytic cell line, THP-1. FEMS Immunol. Med. Microbiol. 1998, 21, 223–230. [Google Scholar] [PubMed] [Green Version]
  98. Thompson, A.; Griffiths, J.S.; Walker, L.; da Fonseca, D.M.; Lee, K.K.; Taylor, P.R.; Gow, N.A.R.; Orr, S.J. Dependence on dectin-1 varies with multiple Candida species. Front. Microbiol. 2019, 10, 1800. [Google Scholar] [CrossRef] [Green Version]
  99. Zhu, J.; Yamane, H.; Paul, W.E. Differentiation of effector CD4 T cell population. Annu. Rev. Immunol. 2010, 28, 445–489. [Google Scholar] [CrossRef] [Green Version]
  100. Iwasaki, A.; Medzhitov, R. Regulation of adaptive immunity by the innate immune system. Science 2010, 327, 291–295. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  101. Veldhoen, M.; Hocking, R.K.; Atkins, R.; Locksley, M.; Stockinger, B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17 producing T cells. Immunity 2006, 24, 179–189. [Google Scholar] [CrossRef] [Green Version]
  102. Osorio, F.; LeibundGut-Landmann, S.; Lochner, M.; Lahl, K.; Sparwasser, T.; Eberl, G.; Sousa, C.R. DC activated via dectin-1 convert Treg into IL-17 producers. Eur. J. Immunol. 2008, 38, 3274–3281. [Google Scholar] [CrossRef]
  103. Campuzano, A.; Zhang, H.; Ostroff, G.R.; Dias, L.D.S.; Wuthrich, M.; Klein, B.S.; Yu, J.-J.; Lara, H.H.; Lopez-Ribot, J.L.; Hung, C.-Y. CARD9-associated dectin-1 and dectin-2 are required for protective immunity of a multivalent vaccine against Coccidioides posadii infection. J. Immunol. 2020, 204, 3296–3306. [Google Scholar] [CrossRef]
  104. Cunha, C.; Di Lanni, M.; Bozza, S.; Giovannini, G.; Zagarella, S.; Zelante, T.; D’Angelo, C.; Pierini, A.; Pitzurra, L.; Falzetti, F.; et al. Detin-1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient- and donor-dependent mechanisms of antifungal immunity. Blood 2010, 116, 5394–5402. [Google Scholar] [CrossRef]
  105. Ferwerda, B.; Ferwerda, G.; Plantinga, T.S.; Willment, J.A.; van Spriel, A.B.; Venselaar, H.; Elbers, C.C.; Johnson, M.D.; Cambi, A.; Huysamen, C.; et al. Human dectin-1 deficiency and mucocutaneous fungal infections. N. Engl. J. Med. 2009, 361, 1760. [Google Scholar] [CrossRef] [Green Version]
  106. Conti, H.R.; Shen, F.; Nayyar, N.; Stocum, E.; Sun, J.N.; Lindemann, M.J.; Ho, A.W.; Hai, J.H.; Yu, J.J.; Jung, J.W. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J. Exp. Med. 2009, 206, 299–311. [Google Scholar] [CrossRef]
  107. Huang, H.; Na, L.; Fidel, P.L.; Schwarzenberger, P. Requirement for interleukin-17A for systemic anti-Candida albicans host defense in mice. J. Infect. Dis. 2004, 190, 624–631. [Google Scholar] [CrossRef] [Green Version]
  108. LeibunGut-Landmann, S.; Osorio, F.; Brown, G.D.; Sousa, C.R. Stimulation of dendritic cells via the dectin-1/Syk pathway allows priming of cytotoxic T-cell responses. Blood 2008, 112, 4971–4980. [Google Scholar] [CrossRef] [Green Version]
  109. Agrawal, S.; Gupta, S.; Agrawal, A. Human dendritic cells activated via dectin-1 are efficient at priming Th17, cytotoxic CD8 T and B cell responses. PLoS ONE 2010, 5, e13418. [Google Scholar] [CrossRef]
  110. Lesley, R.; Kelly, L.M.; Xu, Y.; Cyster, J.G. Naïve CD4 T cells constitutively express CD40L and augment autoreactive B cell survival. Proc. Natl. Acad. Sci. USA 2006, 103, 10717–10722. [Google Scholar] [CrossRef] [Green Version]
  111. Sokol, H.; Conway, K.L.; Zhang, M.; Choi, M.; Morin, B.; Cao, Z.; Villablanca, E.; Li, C.; Wijmenga, C.; Yun, S.H.; et al. Card9 mediates intestinal epithelial cell restitution, T-helper 17 responses, and control of bacterial infection in mice. Gastroenterology 2013, 145, 591–601. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Rahabi, M.; Jacquemin, G.; Prat, M.; Meunier, E.; AlaEddine, M.; Bertrand, B.; Lefevre, L.; Benmoussa, K.; Batigne, P.; Aubouy, A.; et al. Divergent roles for macrophages C-type lectin receptors, dectin-1 and mannose receptors, in the intestinal inflammatory response. Cell Rep. 2020, 30, 4386–4398. [Google Scholar] [CrossRef]
  113. Ross, G.D.; Cain, J.A.; Lachmann, P.J. Membrane complement receptor type three (CR3) has lectin-like properties analogous to bovine conglutinin and function as a receptor for zymosan and rabbit erythrocytes as well as a receptor iC3b. J. Immunol. 1985, 134, 3307. [Google Scholar]
  114. Cain, J.A.; Newmann, S.L.; Ross, D.G. Role of complement receptor type three and serum opsonins in the neutrophil response to yeast. Complementary 1987, 4, 75–86. [Google Scholar] [CrossRef] [PubMed]
  115. Xia, Y.; Vetvicka, V.; Yan, J.; Hanikyrova, M.; Mayadas, T.; Ross, D.G. The β-glucan-binding lectin site of mouse CR3 (CD11b/CD18) and its function in generating a primed state of the receptor that mediates cytotoxic activation in response to iC3b-opsonized target cells. J. Immunol. 1999, 162, 2281–2290. [Google Scholar]
  116. Vetvicka, V.; Thornton, B.P.; Ross, D.G. Soluble beta-guan polysaccharide binding to the lectin site of neutrophil or natural killer cell complement receptor type 3 (CD11b/CD18) generates a primed state of the receptor capable of mediating cytotoxicity of iC3b-opsonized target cells. J. Clin. Investig. 1996, 98, 50–61. [Google Scholar] [CrossRef] [Green Version]
  117. Qi, C.; Cai, Y.; Gunn, L.; Ding, C.; Li, B.; Kloecker, G.; Qian, K.; Vasilakos, J.; Saijo, S.; Iwakura, Y.; et al. Differential pathways regulating innate and adaptive antitumor immune response by particulate and soluble yeast-derived β-glucans. Blood 2011, 117, 6825–6836. [Google Scholar] [CrossRef]
  118. Van Bruggen, R.; Drewniak, A.; Jansen, M.; Van Houdt, M.; Roos, D.; Chapel, H.; Verhoeven, A.J.; Kuijpers, T.W. Complement receptor 3, not dectin-1, is the major receptor on human neutrophils for β-glucan-bearing particles. Mol. Immunol. 2009, 47, 575–581. [Google Scholar] [CrossRef]
  119. Gandezam, R.P.; van Hamme, J.L.; Tool, A.T.; van Houdt, M.; Verkuijlen, P.J.J.H.; Herbst, M.; Liese, J.G.; van de Veerdonk, F.L.; Roos, D.; van de Berg, T.K. Two independent killing mechanisms of Candida albicans by human neutrophils: Evidence from innate immune defects. Blood 2014, 124, 590–597. [Google Scholar]
  120. Teschner, D.; Cholaszczyriska, A.; Ries, F.; Beckert, H.; Theobald, M.; Grabbe, S.; Radsak, M.; Bros, M. CD11b regulates fungal outgrowth but not neutrophil recruitment in a mouse model of invasive pulmonary aspergillosis. Front. Immunol. 2019, 10, 123. [Google Scholar] [CrossRef] [Green Version]
  121. Li, D.; Bai, C.; Zhang, Q.; Li, Z.; Shao, D.; Li, X. β-1,3-glucan/CR3/SYK pathway-dependent LC3B-II accumulation enhanced the fungicidal activity in human neutrophils. J. Microbiol. 2019, 57, 263–270. [Google Scholar] [CrossRef]
  122. Pasquale, E.B. The Eph family of receptors. Curr. Opin. Cell. Biol. 1997, 9, 608–615. [Google Scholar] [CrossRef]
  123. Paavilainen, S.; Grandy, D.; Karelehto, E.; Chang, E.; Susi, P.; Erdjument-Bromage, H.; Nikolov, D.; Himanen, J. High-level expression of a full-length Eph receptor. Protein Expr. Purif. 2013, 92, 112–118. [Google Scholar] [CrossRef] [Green Version]
  124. Kania, A.; Klein, R. Mechanism of ephrin-eph signaling in development, physiology and disease. Nat. Rev. Mol. Cell. Biol. 2016, 17, 240–256. [Google Scholar] [CrossRef] [PubMed]
  125. Zeng, G.; Hu, Z.; Kinch, M.S.; Pan, C.-X.; Flockhart, D.A.; Kao, C.; Gardner, T.A.; Zhang, S.; Li, L.; Baldridge, L.A.; et al. High-level expression of EphA2 receptor tyrosine kinase in prostatic intraepithelial neoplasia. Am. J. Pathol. 2003, 163, 2271–2276. [Google Scholar] [CrossRef] [Green Version]
  126. Miyazaki, T.; Kato, H.; Fukuchi, M.; Nakajima, M.; Kuwano, H. EphA2 overexpression correlates with poor prognosis in esophageal squamous cell carcinoma. Int. J. Cancer 2003, 103, 657–663. [Google Scholar] [CrossRef]
  127. Charmsaz, S.; Beckett, K.; Smith, F.M.; Bruedigam, C.; Moore, A.S.; Al-Ejeh, F.; Lane, S.W.; Boyd, A.W. EphA2 is a therapy target in EphA2-positive leukemias but is not essential for normal hematopoiesis or leukemia. PLoS ONE 2015, 10, e0130692. [Google Scholar] [CrossRef] [Green Version]
  128. Kinch, M.S.; Moore, M.-B.; Harpole, D.H., Jr. Predictive value of the EphA2 receptor tyrosine kinase in lung cancer recurrence and survival. Clin. Cancer. Res. 2003, 9, 613–618. [Google Scholar]
  129. Merritt, W.M.; Thaker, P.H.; Landen, C.N., Jr.; Deavers, M.T.; Fletcher, M.S.; Lin, Y.G.; Han, L.Y.; Kamat, A.A.; Schmandt, R.; Gershenson, D.M.; et al. Analysis of EphA2 expression and mutant p53 in ovarian carcinoma. Cancer Biol. Ther. 2006, 5, 1357–1360. [Google Scholar] [CrossRef] [Green Version]
  130. Herrem, C.J.; Tatsumi, T.; Olson, K.S.; Shirai, K.; Finke, J.H.; Bukowski, R.M.; Zhou, M.; Richmond, A.L.; Derweesh, I.; Kinch, M.S.; et al. Expression of EphA2 is prognostic of disease-free interval and overall survival in surgically treated patients with renal cell carcinoma. Clin. Cancer Res. 2005, 11, 226–231. [Google Scholar]
  131. Holm, R.; Van de Putte, G.; Suo, Z.; Lie, A.K.; Kristensen, G.B. Expressions of EphA2 and EphrinA-1 in early squamous cell cervical carcinomas and their relation to prognosis. Int. J. Med. Sci. 2008, 5, 121–126. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  132. Zelinski, D.P.; Zantek, N.D.; Stewart, J.C.; Irizarry, A.R.; Kinch, M.S. EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res. 2001, 61, 2301–2306. [Google Scholar] [PubMed]
  133. Hong, J.Y.; Shin, M.H.; Chung, K.S.; Kim, E.Y.; Jung, J.Y.; Kang, Y.A.; Kim, Y.S.; Kim, S.K.; Chang, J.; Park, M.S. EphA2 receptor signaling mediates inflammatory responses in lipopolysaccharide-induced lung injury. Tuberc. Respir. Dis. 2015, 78, 218–226. [Google Scholar] [CrossRef]
  134. Thundyil, J.; Manzanero, S.; Pavlovski, D.; Cully, T.R.; Lok, K.Z.; Widiapradja, A.; Chunduri, P.; Jo, D.G.; Naruse, C.; Asano, M.; et al. Evidence that the EphA2 receptor exacerbates ischemic brain injury. PLoS ONE 2013, 8, e53528. [Google Scholar]
  135. Moyes, D.L.; Runglall, M.; Murciano, C.; Shen, C.; Nayar, D.; Thavaraj, S.; Kohli, A.; Islam, A.; Mora-Montes, H.; Challacombe, S.J.; et al. A biphasic innate immune MAPK response discriminates between the yeast and hyphal forms of Candida albicans in epithelial cells. Cell Host Microbe 2010, 8, 225–235. [Google Scholar] [CrossRef] [Green Version]
  136. Abusleme, L.; Diaz, P.I.; Freeman, A.F.; Greenwell-Wild, T.; Brenchley, L.; Desai, J.V.; Ng, W.-I.; Holland, S.M.; Lionakis, M.S.; Segre, J.A.; et al. Human defects in STAT3 promote oral mucosal fungal and bacterial dysbiosis. JCI Insight 2018, 3, e122061. [Google Scholar] [CrossRef]
  137. Swidergall, M.; Solis, N.V.; Wang, Z.; Phan, Q.T.; Marshall, M.E.; Lionakis, M.S.; Pearlman, E.; Filler, S.G. EphA2 is a neutrophil receptor for Candida albicans that stimulates antifungal activity during oropharyngeal infection. Cell Rep. 2019, 28, 423–433. [Google Scholar] [CrossRef]
  138. Swidergall, M.; Solis, N.V.; Millet, N.; Huang, M.Y.; Lin, J.; Phan, Q.T.; Lazarus, M.D.; Wang, Z.; Yeaman, M.R.; Mitchell, A.P.; et al. Activation of EphA2-EGFR signaling in oral epithelial cells by Candida albicans virulence factors. PLoS Pathog. 2021, 17, e1009221. [Google Scholar] [CrossRef] [PubMed]
  139. Verma, A.H.; Richardson, J.P.; Zhou, C.; Coleman, B.M.; Moyes, D.L.; Ho, J.; Hupper, A.R.; Ramani, K.; McGreachy, M.J.; Mufazalov, I.A.; et al. Oral epithelial cells orchestrate innate type 17 responses to Candida albicans through the virulence factor candidalysin. Sci. Immunol. 2017, 2, eaam8834. [Google Scholar] [CrossRef] [Green Version]
  140. Zimmerman, J.W.; Lindermuth, J.; Fish, P.A.; Palace, G.P.; Stevenson, T.T.; DeMong, D.E. A novel carbohydrate- glycosphingolipid interaction between a β-(1-3)-glucan immunomodulator, PGG-glucan, and lactosylceramide of human leukocytes. J. Biol. Chem. 1998, 273, 22014. [Google Scholar] [CrossRef] [Green Version]
Ijms 22 04778 g001 550
Figure 1. Dectin-1 Signaling Pathway. (A) Upon beta-glucan binding, dectin-1 recruits Syk to the hemi-ITAM followed by the activation of the CARD9-BCL10-MALT1 (CBM) complex. As a result, the NF-kB pathway is activated, and genes coding proinflammatory cytokines (TNF-α, IL-6, IL-1β), are released to promote the maturation of dendritic cells, and differentiation of Th1/Th17 cells. ROS production is also induced in a Syk-dependent manner, resulting in inflammasome and activation of caspase-1. All these downstream events of dectin-1 finally contribute to the eradication of fungi. (B) Raf-1 is activated in a Syk-independent manner and induces deactivation of RelB and activation of NF-kB pathway. (C) Dectin-1 collaborates with calcium-mediated pathways to activate ERK-MAPK, cAMP response element binding protein (CREB), and induce cytokines including TNF-α, and IL-10. (D) Dectin-1 collaborates with tetraspanin-like molecules, binds beta-glucan, and transduces signals. (E) CD82 colocalize with dectin-1 during beta-glucan binding, and induces inflammatory cytokines and ROS to boost anti-fungal immunity. MS4A4A also binds to dectin-1 when dectin-1 binds beta-glucan or glycoprotein on cancer cells, and enhances IL-6 cytokine production from macrophages, IFN-γ production, and contributes to anti-cancer immunity.
Figure 1. Dectin-1 Signaling Pathway. (A) Upon beta-glucan binding, dectin-1 recruits Syk to the hemi-ITAM followed by the activation of the CARD9-BCL10-MALT1 (CBM) complex. As a result, the NF-kB pathway is activated, and genes coding proinflammatory cytokines (TNF-α, IL-6, IL-1β), are released to promote the maturation of dendritic cells, and differentiation of Th1/Th17 cells. ROS production is also induced in a Syk-dependent manner, resulting in inflammasome and activation of caspase-1. All these downstream events of dectin-1 finally contribute to the eradication of fungi. (B) Raf-1 is activated in a Syk-independent manner and induces deactivation of RelB and activation of NF-kB pathway. (C) Dectin-1 collaborates with calcium-mediated pathways to activate ERK-MAPK, cAMP response element binding protein (CREB), and induce cytokines including TNF-α, and IL-10. (D) Dectin-1 collaborates with tetraspanin-like molecules, binds beta-glucan, and transduces signals. (E) CD82 colocalize with dectin-1 during beta-glucan binding, and induces inflammatory cytokines and ROS to boost anti-fungal immunity. MS4A4A also binds to dectin-1 when dectin-1 binds beta-glucan or glycoprotein on cancer cells, and enhances IL-6 cytokine production from macrophages, IFN-γ production, and contributes to anti-cancer immunity.
Ijms 22 04778 g001
Ijms 22 04778 g002 550
Figure 2. Beta-glucans may regulate intestinal homeostasis. Presence of the commensal fungi, Candida tropicalis enhances the susceptibility of dectin-1 KO mice to DSS-induced colitis by impairing the fungal killing activity of DCs and macrophages, and further activation of T cells, neutrophils by cytokines and chemokines from DCs and macrophages. This in turn enhances further growth of Candida tropicalis [58,111].
Figure 2. Beta-glucans may regulate intestinal homeostasis. Presence of the commensal fungi, Candida tropicalis enhances the susceptibility of dectin-1 KO mice to DSS-induced colitis by impairing the fungal killing activity of DCs and macrophages, and further activation of T cells, neutrophils by cytokines and chemokines from DCs and macrophages. This in turn enhances further growth of Candida tropicalis [58,111].
Ijms 22 04778 g002
Ijms 22 04778 g003 550
Figure 3. Alternative receptors of β-glucan. CR3 (hetero-complex of CD11b/Integrin αM and CD18/Integrin β2) and EphA2 are known to induce phagocytosis of beta-glucan particles or fungi, oxidative burst, and production of inflammatory cytokines, suggesting that they are functional receptors for beta-glucan in anti-fungal immunity. LacCer is also known to bind beta-glucan, however, its precise function in beta-glucan signaling is presently unknown.
Figure 3. Alternative receptors of β-glucan. CR3 (hetero-complex of CD11b/Integrin αM and CD18/Integrin β2) and EphA2 are known to induce phagocytosis of beta-glucan particles or fungi, oxidative burst, and production of inflammatory cytokines, suggesting that they are functional receptors for beta-glucan in anti-fungal immunity. LacCer is also known to bind beta-glucan, however, its precise function in beta-glucan signaling is presently unknown.
Ijms 22 04778 g003
Table
Table 1. In vivo studies of fungal infection using beta-glucan receptor (related) gene-deficient mice.
Table 1. In vivo studies of fungal infection using beta-glucan receptor (related) gene-deficient mice.
ReceptorAllele SymbolGenetic BackgroundFungusJournalRef.
Dectin-1Clec7a <tm1Yiw>C57BL/6J, BALB/cCandida albicans, Pneumocystis cariniiNat Immunol. 2007[25]
Clec7a <tm1Gdb>B6;129 mixC.albicansNat Immunol. 2007[24]
Clec7a <tm1Yiw>C57BL/6JCryptococcus neoformansMicrobiol Immunol. 2007[53]
Clec7a <tm1Gdb>129/SvEvAspergillus fumigatusJ Immunol. 2009[54]
Lyz2 <tm1(cre)Ifo>. Clec7a <tm1.1Bpip>: *C57BL/6JC.albicansPLoS Pathog. 2010[55]
Clec7a <tm1Yiw>C57BL/6JA. fumigatusJ Exp Med. 2011[56]
Clec7a <tm1Yiw>BALB/cA. fumigatusPLoS One 2011[57]
Clec7a <tm1Gdb>C57BL/6Candida tropicalisScience 2012[58]
Clec7a <tm1Gdb>C57BL/6, (C57BL/6;DBA/2)F2Coccidioides immitismBio 2013[59]
Clec7a <tm1Gdb>C57BL/6Paracoccidioides brasiliensisJ Infect Dis. 2014[60]
Clec7a <tm1Yiw>C57BL/6JC. tropicalisCell Host Microbe 2015[61]
Clec7a <tm1Gdb>, Clec7a <tm1Gdb>. Itgam <tm1Myd>C57BL/6Histoplasma capsulatumPLoS Pathog. 2015[62]
Clec7a <tm1Yiw>C57BL/6JTrichosporon asahiiInflamm Res. 2016[63]
Clec7a <tm1Yiw>C57BL/6JTrichophyton rubrumInnate Immun. 2016[64]
Clec7a <tmX>: **C57BL/6Blastomyces dermatitidisJ Clin Invest. 2016[65]
Clec7a <tm1Gdb>C57BL/6C.albicance, Candida kruseiAm J Transl Res. 2019[66]
Itgam <tm1Myd>C57BL/6B. dermatitidisJ Immunol. 2004[67]
Itgam <tm1Myd>C57BL/6C.albicansCell Host Microbe. 2011[68]
Itgam <tm1Bll>C57BL/6JC.albicansInfect Immun. 2011[69]
CR3Itgb2 <tm2Bay>C57BL/6JA. fumigatusJ Clin Invest. 2012[70]
Itgam <tm1Myd>, Clec7a <tm1Gdb>. Itgam <tm1Myd>C57BL/6H. capsulatumPLoS Pathog. 2015[62]
Itgam <tm1Myd>C57BL/6C. neoformansNat Commun. 2019[71]
Itgam <tm1Myd>C57BL/6A. fumigatusFront Immunol. 2019[72]
EphA2Epha2 <tm1Jrui>C57BL/6C.albicansNat Microbiol. 2018[73]
CD82Cd82 <tm1.1Cmir>C57BL/6C.albicansJ Immunol. 2019[51]
* Macrophage-specific conditional knock-out. ** Undescribed.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Desamero, M.J.M.; Chung, S.-H.; Kakuta, S. Insights on the Functional Role of Beta-Glucans in Fungal Immunity Using Receptor-Deficient Mouse Models. Int. J. Mol. Sci. 2021, 22, 4778. https://doi.org/10.3390/ijms22094778

AMA Style

Desamero MJM, Chung S-H, Kakuta S. Insights on the Functional Role of Beta-Glucans in Fungal Immunity Using Receptor-Deficient Mouse Models. International Journal of Molecular Sciences. 2021; 22(9):4778. https://doi.org/10.3390/ijms22094778

Chicago/Turabian Style

Desamero, Mark Joseph Maranan, Soo-Hyun Chung, and Shigeru Kakuta. 2021. "Insights on the Functional Role of Beta-Glucans in Fungal Immunity Using Receptor-Deficient Mouse Models" International Journal of Molecular Sciences 22, no. 9: 4778. https://doi.org/10.3390/ijms22094778

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop