Recognition of fungal RNA by TLR7 has a nonredundant role in host defense against experimental candidiasis
Recognition of fungal RNA by TLR7 has a nonredundant role in host defense against experimental candidiasis
复制标题
DOI：
10.1002/eji.201242532
复制
发表时间：
2012-10-01
影响因子：
5.4
通讯作者：
Beninati, Concetta
中科院分区：
文献类型：
--
作者：
Biondo, Carmelo;Malara, Antonio;Beninati, Concetta
尽管有令人信服的证据表明Toll样受体（TLR）家族成员参与真菌识别，但对单个TLR在抗真菌防御中的功能作用知之甚少。我们发现TLR 7是白念珠菌和酿酒酵母诱导IL-12（IL-12 p70）的部分必需因子。此外，IL-12 p70反应在来自3d小鼠的细胞中完全消除，其不能将TLR移动到内体区室，以及在来自缺乏TLR衔接子MyD 88或IRF 1转录因子的小鼠的细胞中。值得注意的是，纯化的真菌RNA再现了完整酵母的IL-12 p70诱导。尽管RNA也可以诱导中度的TLR 7依赖性IL-23和肿瘤坏死因子-α（TNF-α）分泌，但TLR 7和其他内体TLR对于整个真菌的IL-23或TNF-α诱导是多余的。重要的是，缺乏TLR 7或IRF 1的小鼠对系统性C.白色念珠菌感染我们的数据表明，IRF 1是一种新的，非冗余的真菌识别途径，RNA作为一个主要的目标，并需要吞噬体招募细胞内的TLR的下游。该途径不同于参与IL-23或TNF-α应答的那些途径，我们在此显示其独立于细胞内TLR的易位、吞噬作用或吞噬体酸化。
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-a) secretion, TLR7 and other endosomal TLRs were redundant for IL-23 or TNF-a 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-a responses, which we show here to be independent from translocation of intracellular TLRs, phagocytosis, or phagosomal acidification.