Recognition of yeast nucleic acids triggers a host‐protective type I interferon response

Abstract

Although type I interferons (IFN-a/b) have been traditionally associated with antiviral responses, their importance in host defense against bacterial pathogens is being increasingly appreciated. Little is known, however, about the occurrence and functional role of IFN-a/b production in response to pathogenic yeasts. Here, we found that conventional DCs, but not macrophages nor plasmacytoid DCs, mounted IFN-b responses after in vitro stimulation with Candida spp. or Saccharomyces cerevisiae. These responses absolutely required MyD88, a Toll-like receptor (TLR) adaptor molecule, and were partially dependent on TLR9 and TLR7. Moreover, Candida DNA, as well as RNA, could recapitulate the IFN-b response. After intravenous challenge with Candida albicans, most mice lacking the IFN-a/b receptor died from their inability to control fungal growth, whereas all WT controls survived. These data suggest that recognition of yeast nucleic acids by TLR7 and TLR9 triggers a host-protective IFN-a/b response.Key words: Candida albicans . Cytokines . DCs . Fungal infections . Macrophages Supporting Information available online IntroductionCandida albicans (C. albicans) is, among fungi, the most common pathogen of humans. Although they are normally harmless commensals of the intestinal and urinary tract, C. albicans and other Candida species can cause recurrent mucosal infections in otherwise healthy subjects and life-threatening conditions in hospitalized or immunocompromised patients [1]. In recent years, C. albicans has become the fourth most common cause of bloodstream infections, with an incidence of between 1 and 24 cases per 100 000 and a mortality rate of 30-50% [2]. Since the host immune status is the major factor that determines the transition of C. albicans from commensalism to pathogenicity, elucidating the mechanisms underlying immune response initiation, particularly those underlying recognition of fungal components, is crucial to developing new and more effective strategies to combat these infections. In fact, despite the availability of new classes of antifungal drugs, current available therapies are only partially effective and are associated with significant side effects.Antimicrobial responses are initiated by the activation of germ-line-encoded receptors (pattern-recognition receptors, PRRs) expressed by cells of the innate immune system, mainly by macrophages and DCs, which monitor potential portals of pathogen entry. Each PRR binds directly or indirectly to one or more evolutionary conserved microbial molecules (pathogenassociated molecular patterns, PAMPs) and triggers intracellular signal transduction cascades culminating in distinctive transcriptional and nontranscriptional responses. By this mechanism, PRRs link microbial recognition with the selective activation of specific arms of the innate immune system [3].Ã These authors have contributed equally to this study. Eur. J. Immunol. 2011. 41: 1969-1979 DOI 10.1002 Immunity to infection 1969Considerable progress has been recently made in the identification ...

The role of pattern recognition receptors in the innate recognition ofCandida albicans

“…126 TLR7 is required for the recognition of single-stranded RNA from C. albicans and the mice lacking TLR7 were hypersusceptible to systemic C. albicans infection. 26,27 Of note, inflammasome plays an important role in antifungal immune response. Inflammasome is a cytoplasmic proteolytic multimeric protein complex expressed in myeloid cells, and consists of NLRs and several adaptors.…”

“…TLR7 is required for the recognition of single-stranded RNA of C. albicans. 26,27 Of note, some CLRs are involved in the recognition of C. albicans, including Dectin-1, Dectin-2, Dectin-3 (originally named murine macrophage C-type lectin, MCL), the dendritic cell-specific ICAM3-grabbing non-integrin (DC-SIGN), the macrophage mannose receptor (MR), Galectin-3, and the macrophage-inducible C-type lectin (Mincle). 28,29 Dectin-1 recognizes b-(1,3)-glucan, while the rest CLRs recognize different mannose-relative structures.…”

Induction of Caspase-11 by Aspartyl Proteinases of Candida albicans and Implication in Promoting Inflammatory Response

“…These studies demonstrated that type I IFN induces severe kidney damage by promoting excessive recruitment and activation of inflammatory monocytes and neutrophils. However, other reports suggest that type I IFN can be beneficial as part of the host immune response to C. albicans (28,31). Other studies related to sepsis show that type I IFN plays a critical role in promoting lethal endotoxemia (32,33).…”

Recognition of pathogen-associated nucleic acids by endosomal nucleic acid-sensing toll-like receptors

“…Unmethylated CpG motifs in A. fumigatus DNA stimulate mouse bone marrow-derived DCs (BMDCs) and human pDCs to secrete inflammatory cytokines in a TLR9-dependent manner [132], contributing to the establishment of anti-fungi immune response states. In addition to A. fumigatus, Candida albicans, S. cerevisiae, Malassezia furfur, and Cryptococcus neoformans DNAs are capable of triggering TLR9 recruitment, demonstrating that TLR9 is compartmentalized selectively to fungal phagosomes and negatively modulates macrophage antifungal effector functions [108,109,133]. Interestingly, hemozoin, a crystalline metabolite of hemoglobin produced by Plasmodium falciparum, acts as an inducer of TLR9 and potently activates macrophages and DCs to produce inflammatory cytokines and chemokines [130].…”

“…Recent studies also showed that IFN-a/b is induced by Candida spp. and Saccharomyces cerevisiae RNA/DNA by a mechanism that involves endosomal recognition of fungal RNA and DNA by TLR7 and TLR9, respectively, and absolutely requires MyD88 [108,109].…”