Oral epithelial cells orchestrate innate type 17 responses to Candida albicans through the virulence factor candidalysin.
Oral epithelial cells orchestrate innate type 17 responses to Candida albicans through the virulence factor candidalysin.
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DOI：
10.1126/sciimmunol.aam8834
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发表时间：
2017-11-03
影响因子：
24.8
通讯作者：
Gaffen SL
中科院分区：
文献类型：
--
作者：
Verma AH;Richardson JP;Zhou C;Coleman BM;Moyes DL;Ho J;Huppler AR;Ramani K;McGeachy MJ;Mufazalov IA;Waisman A;Kane LP;Biswas PS;Hube B;Naglik JR;Gaffen SL
白色念珠菌是一种双态共生真菌，可引起免疫缺陷患者严重的口腔感染。白色念珠菌菌丝侵入口腔上皮是一个重要的毒力特征。对白色念珠菌的先天免疫和适应性免疫都需要IL-17信号。在先天应答过程中，IL-17由γδ-T细胞和一群鲜为人知的先天作用CD4+TCRαβ+细胞产生，但在急性感染期间只有TCRαβ+细胞扩增。证实了这些细胞的先天性质，在最初的反应中，TCR没有被检测到被激活，Nur77eGFP小鼠报告了抗原特异性信号通过TCR。相反，先天TCRαβ+细胞的扩增是由内源性和外源性IL-1R信号驱动的。出乎意料的是，不需要CCR6/ ccl20依赖性募集或原型真菌模式识别受体。然而，不能从酵母切换到菌丝的白色念珠菌突变体显示TCRαβ+细胞增殖和Il17a表达受损。这促使我们评估念珠菌素的作用，念珠菌素是一种菌丝相关肽，可损害口腔上皮细胞并引发炎性细胞因子（包括IL-1）的产生。事实上，念珠菌素缺乏的菌株未能上调Il17a或驱动先天TCRαβ+细胞的增殖。此外，念珠菌素与IL-17协同信号，进一步增强IL-1α/β和其他细胞因子的表达。因此，IL-17和白色念珠菌通过分泌念珠菌素，在自我强化的前馈循环中放大炎症。这些发现挑战了菌丝形成本身是口腔先天应答所必需的范式，并证明了IL-1和il -17依赖性先天免疫的建立是由组织损伤性菌丝诱导的。
Candida albicans is a dimorphic commensal fungus that causes severe oral infections in immunodeficient patients. Invasion of C. albicans hyphae into oral epithelium is an essential virulence trait. IL-17 signaling is required for both innate and adaptive immunity to C. albicans. During the innate response, IL-17 is produced by γδ-T cells and a poorly understood population of innate-acting CD4+TCRαβ+ cells, but only the TCRαβ+ cells expand during acute infection. Confirming the innate nature of these cells, the TCR was not detectably activated during the primary response, evidenced by Nur77eGFP mice that report antigen-specific signaling through the TCR. Rather, expansion of innate TCRαβ+ cells was driven by both intrinsic and extrinsic IL-1R signaling. Unexpectedly, there was no requirement for CCR6/CCL20-dependent recruitment or prototypical fungal pattern recognition receptors. However, C. albicans mutants that cannot switch from yeast to hyphae showed impaired TCRαβ+ cell proliferation and Il17a expression. This prompted us to assess the role of Candidalysin, a hyphal-associated peptide that damages oral epithelial cells and triggers production of inflammatory cytokines including IL-1. Indeed, Candidalysin-deficient strains failed to upregulate Il17a or drive proliferation of innate TCRαβ+ cells. Moreover, Candidalysin signaled synergistically with IL-17, which further augmented expression of IL-1α/β and other cytokines. Thus, IL-17 and C. albicans, via secreted Candidalysin, amplify inflammation in a self-reinforcing feed-forward loop. These findings challenge the paradigm that hyphal formation per se is required for the oral innate response, and demonstrate that establishment of IL-1- and IL-17-dependent innate immunity is induced by tissue-damaging hyphae.
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影响因子：
4.4
作者：
Baer, Eva;Gadiator, Andre;LeibundGut-Landmann, Salome
通讯作者：
LeibundGut-Landmann, Salome
影响因子：
4.4
作者：
Claudio, Estefania;Sonder, Soren Ulrik;Saret, Sun;Carvalho, Gabrielle;Ramalingam, Thirumalai R.;Wynn, Thomas A.;Chariot, Alain;Garcia-Perganeda, Antonio;Leonardi, Antonio;Paun, Andrea;Chen, Amy;Ren, Nina Y.;Wang, Hongshan;Siebenlist, Ulrich
通讯作者：
Siebenlist, Ulrich
对真菌病原体的先天防御。
影响因子：
5.4
作者：
Drummond RA;Gaffen SL;Hise AG;Brown GD
通讯作者：
Brown GD
影响因子：
32.4
作者：
Kashem SW;Riedl MS;Yao C;Honda CN;Vulchanova L;Kaplan DH
通讯作者：
Kaplan DH
影响因子：
3.1
作者：
Ferreira, Maria Carolina;Whibley, Natasha;Gaffen, Sarah L.
通讯作者：
Gaffen, Sarah L.