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Sci Immunol. 2017 Nov 3;2(17). pii: eaam8834. doi: 10.1126/sciimmunol.aam8834.

Oral epithelial cells orchestrate innate type 17 responses to Candida albicans through the virulence factor candidalysin.

Author information

1
Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
2
Mucosal and Salivary Biology Division, Dental Institute, King's College London, London, UK.
3
Centre for Host-Microbiome Interactions, Mucosal and Salivary Biology Division, Dental Institute, King's College London, London, UK.
4
Department of Pediatrics, Children's Research Institute, Children's Hospital and Health System, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
5
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University of Mainz, Mainz, Germany.
6
Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
7
Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology-Hans Knoell Institute, Jena, Germany.
8
Friedrich-Schiller University, Jena, Germany.
9
Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
10
Mucosal and Salivary Biology Division, Dental Institute, King's College London, London, UK. sarah.gaffen@pitt.edu julian.naglik@kcl.ac.uk.
11
Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA. sarah.gaffen@pitt.edu julian.naglik@kcl.ac.uk.

Abstract

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 γδ T cells and a poorly understood population of innate-acting CD4+ αβ T cell receptor (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, as evidenced by Nur77eGFP mice that report antigen-specific signaling through the TCR. Rather, the 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. Candidalysin-deficient strains failed to up-regulate Il17a or drive the proliferation of innate TCRαβ+ cells. Moreover, candidalysin signaled synergistically with IL-17, which further augmented the 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.

PMID:
29101209
PMCID:
PMC5881387
DOI:
10.1126/sciimmunol.aam8834
[Indexed for MEDLINE]
Free PMC Article

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