Recognition of fungal RNA by TLR7 has a nonredundant role in host defense against experimental candidiasis

Abstract

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.

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

“…However, when challenged with higher doses, no significant difference was observed between TLR7-deficient mice and wild-type mice. 27 Similarly, using high dose challenges, TLR9-/-mice showed no significant alteration in survival upon clinical C. albicans isolate infection. 25,27 However, increased susceptibility to systemic candidiasis and impaired fungal clearance in TLR9-/-mice were observed upon challenge with a lower dose of C. albicans.…”

“…27 Similarly, using high dose challenges, TLR9-/-mice showed no significant alteration in survival upon clinical C. albicans isolate infection. 25,27 However, increased susceptibility to systemic candidiasis and impaired fungal clearance in TLR9-/-mice were observed upon challenge with a lower dose of C. albicans. 27 Taylor PR et al 184 investigatedb-glucan recognition and control of fungal infection using Dectin1-/-mice, and revealed that cytokine release, phagocyte recruitment, phagocytosis and microbial killing are all impaired in the Dectin1-/-mice compared with wild-type mice in disseminated candidiasis model.…”

“…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.…”

“…25,27 However, increased susceptibility to systemic candidiasis and impaired fungal clearance in TLR9-/-mice were observed upon challenge with a lower dose of C. albicans. 27 Taylor PR et al 184 investigatedb-glucan recognition and control of fungal infection using Dectin1-/-mice, and revealed that cytokine release, phagocyte recruitment, phagocytosis and microbial killing are all impaired in the Dectin1-/-mice compared with wild-type mice in disseminated candidiasis model. However, another study carried out by Saijo S et al 185 using Dectin1-/-mice suggested that Dectin-1 is not required for host defense against C. albicans.…”

“…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.…”