Recognition of fungal RNA by TLR7 has a nonredundant role in host defense against experimental candidiasis.
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 mobilize 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 Elie Metchnikoff Department, University of Messina, Messina, Italy.
Carmelo
C
Biondo
Antonio
A
Malara
Alessandro
A
Costa
Giacomo
G
Signorino
Francesco
F
Cardile
Angelina
A
Midiri
Roberta
R
Galbo
Salvatore
S
Papasergi
Maria
M
Domina
Michela
M
Pugliese
Giuseppe
G
Teti
Giuseppe
G
Mancuso
Concetta
C
Beninati
D000818:Animals; D002176:Candida albicans / Q000235:genetics / Q000276:immunology*; D002177:Candidiasis / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology; D004198:Disease Susceptibility; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D007109:Immunity; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D010587:Phagocytosis / Q000235:genetics; D012331:RNA, Fungal / Q000276:immunology*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000235:genetics
D016207:Cytokines; D050856:Interferon Regulatory Factor-1; C494258:Irf1 protein, mouse; D012331:RNA, Fungal; D051199:Toll-Like Receptor 7