Dectin-1 is required for β-glucan recognition and control of fungal infection

Abstract

Abstractβ-Glucan is one of the most abundant polysaccharides in fungal pathogens, yet its importance in antifungal immunity is unclear. Here we show that deficiency of dectin-1, the myeloid receptor for β-glucan, rendered mice susceptible to infection with Candida albicans. Dectin-1-deficient leukocytes demonstrated significantly impaired responses to fungi even in the presence of opsonins. Impaired leukocyte responses were manifested in vivo by reduced inflammatory cell recruitment after fungal infection, resulting in substantially increased fungal burdens and enhanced fungal dissemination. Our results establish a fundamental function for β-glucan recognition by dectin-1 in antifungal immunity and demonstrate a signaling non-Toll-like patternrecognition receptor required for the induction of protective immune responses.Infections with normally nonpathogenic fungi such as Candida albicans are an emerging problem resulting from modern medical interventions and the increasing prevalence of acquired immunodeficiency1. The high incidence of morbidity and mortality associated with such diseases, especially once the fungus has disseminated, demonstrates deficiencies in both present antifungal therapies and understanding of the host immune response. Protection against such organisms is mediated mainly by phagocytic cells that recognize, ingest and kill the invading pathogen, inducing a T helper type 1 immune response, which in turn activates fungicidal effector mechanisms, such as the respiratory burst1. Although cells such as neutrophils and macrophages are thought to be crucial in that process, the mechanism underlying the recognition and initiation of the protective responses to these pathogens remains unclear. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. Europe PMC Funders GroupAuthor Manuscript Nat Immunol. Author manuscript; available in PMC 2007 July 01. Published The cell walls of fungi consist mainly of carbohydrates, including mannose-based structures (the mannoproteins), β-glucan and chitin. For immune systems of infected hosts, such polysaccharides serve as pathogen-associated molecular patterns (PAMPs) that can be recognized by a variety of host-expressed pattern-recognition receptors, including the Tolllike receptors (TLRs), although the precise functions of each of the myriad receptors that can respond to these pathogens and contribute to the induction of protective responses have not been fully elucidated.Historically, the cell walls of fungi were shown to be covered by a layer of mannoproteins, which prompted much interest in mannose-based recognition systems2. Subsequent evidence has suggested that this model may be too simplistic and that other PAMPs, particularly β-glucans, are exposed on the cell surface and therefore are potentially important in immune recognition3. In fungi such as C. albicans and Saccharomyces cerevisiae, β-glucans can comprise up to 50% of the dry weight of the fungal cell wall and are essential structural components that ...

CD8– dendritic cells preferentially cross‐present Saccharomyces cerevisiae antigens

“…We did not find a role for other receptors such as the mannose receptor, SIGNR1, or CR3 (CD11b/CD18), which is in line with other studies [9,29,45]. Furthermore, we observed no requirement for MyD88-dependent signaling for uptake and presentation of yeast antigens to T cells, which is consistent with the observations that phagocytosis, respiratory burst and the production of certain cytokines are TLRindependent and mediated by dectin-1 [18,24,26].…”

“…Furthermore, we observed no requirement for MyD88-dependent signaling for uptake and presentation of yeast antigens to T cells, which is consistent with the observations that phagocytosis, respiratory burst and the production of certain cytokines are TLRindependent and mediated by dectin-1 [18,24,26]. Initial reports stated dectin-1 expression on a fraction of both CD8 + and CD8 -DC subsets [38].…”

“…Dectin-1 recognizes zymosan and Saccharomyces cerevisiae, but also pathogenic fungi like C. albicans, Pneumocystis carinii and A. fumigatus [9,17,[20][21][22]. Recent studies with dectin-1-deficient mice show the importance of dectin-1 for the immune response towards fungal infections in vivo [23,24].…”

“…b-Glucans are conserved cell wall components of fungi and dectin-1 has been shown to recognize many pathogenic fungi like C. albicans, P. carinii and A. fumigatus [9,17,[20][21][22]. Therefore, dectin-1 expression on mouse DC would enable them to induce adaptive immune responses against these pathogens, although this has not extensively been investigated in vivo [23,24].Our study shows that both CD8 + and CD8 -DC subsets phagocytose yeast via dectin-1 recognition of b-glucans, and that both types of DC present yeastderived antigens in an MHC class II-restricted manner. Strikingly, we observed that cross-presentation of yeast antigens in MHC class I is significantly more efficient in CD8 -DC, and that only CD8 -DC produce IL-10, IL-6 and TNF-a and showed increased mRNA levels of IL-23 in response to yeast.…”

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of TH1/TH17 polarization

“…Along with Bcl-10 and MALT1, CARD9 is a crucial mediator in the ITAM-signaling pathway that links recognition of b-glucan by Dectin-1 to NF-kB and MAPK activation [13,14]. Overall, the Syk-CARD9 pathway is essential for promoting Dectin-1-mediated DC responses to fungal infection [15][16][17], in particular the induction of DC maturation and secretion of IL-23, which sustains and amplifies T H 17 CD4 1 T H cell differentiation [18]. Moreover, Dectin-1 stimulation contributes to the conversion of Treg into IL-17 producers [19].…”