Group B streptococcus (GBS) is a frequent agent of life-threatening sepsis and meningitis in neonates and adults with predisposing conditions. We tested the hypothesis that activation of the inflammasome, an inflammatory signaling complex, is involved in host defenses against this pathogen. We show here that murine bone marrow-derived conventional dendritic cells responded to GBS by secreting IL-1β and Il-18. IL-1β release required both pro-IL-1β transcription and caspase-1-dependent proteolytic cleavage of intracellular pro-IL-1β. Dendritic cells lacking the TLR adaptor MyD88, but not those lacking TLR2, were unable to produce pro-IL-1β mRNA in response to GBS. Pro-IL-1β cleavage and secretion of the mature IL-1β form depended on the NOD-like receptor family, pyrin domain containing 3 (NLRP3) sensor and the apoptosis-associated speck-like protein containing a CARD (ASC) adaptor. Moreover, activation of the NLRP3 inflammasome required GBS expression of β-hemolysin, an important virulence factor. We further found that mice lacking NLRP3, ASC or caspase-1 were considerably more susceptible to infection than wild-type mice. Our data link the production of a major virulence factor by GBS with the activation of a highly effective anti-GBS response triggered by the NLRP3 inflammasome.

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 ...

Despite convincing evidence for involvement of members of the Toll‐like receptor (TLR) family in fungal recognition, little is known of the functional role of individual TLRs in antifungal defenses. We found here that TLR7 was partially required for the induction of IL‐12 (IL‐12p70) by Candida albicans or Saccharomyces cerevisiae. Moreover, the IL‐12p70 response was completely abrogated in cells from 3d mice, which are unable to mob‐ilize TLRs to endosomal compartments, as well as in cells from mice lacking either the TLR adaptor MyD88 or the IRF1 transcription factor. Notably, purified fungal RNA recapitulated IL‐12p70 induction by whole yeast. Although RNA could also induce moderate TLR7‐dependent IL‐23 and tumor necrosis factor‐alpha (TNF‐α) secretion, TLR7 and other endosomal TLRs were redundant for IL‐23 or TNF‐α induction by whole fungi. Importantly, mice lacking TLR7 or IRF1 were hypersusceptible to systemic C. albicans infection. Our data suggest that IRF1 is downstream of a novel, nonredundant fungal recognition pathway that has RNA as a major target and requires phagosomal recruitment of intracellular TLRs. This pathway differs from those involved in IL‐23 or TNF‐α responses, which we show here to be independent from translocation of intracellular TLRs, phagocytosis, or phagosomal acidification.