Journal
SCIENCE IMMUNOLOGY
Volume 2, Issue 17, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.aam8834
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Categories
Funding
- NIH [DE022550, DE023815, AI107825, AI103022, AI110822, DK104680]
- Medical Research Council [MR/M011372/1]
- Biotechnology and Biological Sciences Research Council [BB/N014677/1]
- NIH Research at Guys and St. Thomas's NHS Foundation Trust, and the King's College London Biomedical Research Centre [IS-BRC-1215-20006]
- Deutsche Forschungsgemeinschaft (TR/CRC FungiNet Project C1)
- Infect ERA-NET Program (FunComPath) [BMBF 031L0001A]
- H2020-Marie Sklodowska-Curie Actions-European Training Networks-Marie Sklodowska-Curie [642095]
- Medical College of Wisconsin Department of Pediatrics and Children's Hospital of Wisconsin Research Institute
- Deutsche Forschungsgemeinschaft [TR/CRC 128, TR/CRC 156]
- BD LSR Fortessa grant [1S10-OD011925]
- Biotechnology and Biological Sciences Research Council [BB/N014677/1] Funding Source: researchfish
- Medical Research Council [MR/M011372/1] Funding Source: researchfish
- BBSRC [BB/N014677/1] Funding Source: UKRI
- MRC [MR/M011372/1] Funding Source: UKRI
- Marie Curie Actions (MSCA) [642095] Funding Source: Marie Curie Actions (MSCA)
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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 gamma delta T cells and a poorly understood population of innate-acting CD4(+) alpha beta T cell receptor (TCR alpha beta)(+) cells, but only the TCR alpha beta(+) 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 TCR alpha beta(+) 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 TCR alpha beta(+) cell proliferation and ll17a 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 ll17a or drive the proliferation of innate TCR alpha beta(+) cells. Moreover, candidalysin signaled synergistically with IL-17, which further augmented the expression of IL-1 alpha/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.
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