| First Author | Verma AH | Year | 2017 |
| Journal | Sci Immunol | Volume | 2 |
| Issue | 17 | PubMed ID | 29101209 |
| Mgi Jnum | J:260574 | Mgi Id | MGI:6141132 |
| Doi | 10.1126/sciimmunol.aam8834 | Citation | Verma AH, et al. (2017) Oral epithelial cells orchestrate innate type 17 responses to Candida albicans through the virulence factor candidalysin. Sci Immunol 2(17) |
| abstractText | 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. Interleukin-17 (IL-17) signaling is required for both innate and adaptive immunity to C. albicans During the innate response, IL-17 is produced by gammadelta T cells and a poorly understood population of innate-acting CD4(+) alphabeta T cell receptor (TCRalphabeta)(+) cells, but only the TCRalphabeta(+) cells expand during acute infection. Confirming the innate nature of these cells, the TCR was not detectably activated during the primary response, as evidenced by Nur77(eGFP) mice that report antigen-specific signaling through the TCR. Rather, the expansion of innate TCRalphabeta(+) 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 TCRalphabeta(+) 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. Candidalysin-deficient strains failed to up-regulate Il17a or drive the proliferation of innate TCRalphabeta(+) cells. Moreover, candidalysin signaled synergistically with IL-17, which further augmented the expression of IL-1alpha/beta 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. |
