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

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 ?? T cells and a poorly understood population of innate-acting CD4+ ?? T cell receptor (TCR??)+ cells, but only the TCR??+ 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 TCR??+ 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??+ 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 TCR??+ cells. Moreover, candidalysin signaled synergistically with IL-17, which further augmented the expression of IL-1?/? 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.

SUBMITTER: Verma AH

PROVIDER: S-EPMC5881387 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Verma Akash H AH Richardson Jonathan P JP Zhou Chunsheng C Coleman Bianca M BM Moyes David L DL Ho Jemima J Huppler Anna R AR Ramani Kritika K McGeachy Mandy J MJ Mufazalov Ilgiz A IA Waisman Ari A Kane Lawrence P LP Biswas Partha S PS Hube Bernhard B Naglik Julian R JR Gaffen Sarah L SL

Science immunology 20171101 17

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 ...[more]

PMID: 29101209

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Project description:Background & aimsAlcohol-associated liver disease is a leading indication for liver transplantation and a leading cause of mortality. Alterations to the gut microbiota contribute to the pathogenesis of alcohol-associated liver disease. Patients with alcohol-associated liver disease have increased proportions of Candida spp. in the fecal mycobiome, yet little is known about the effect of intestinal Candida on the disease. Herein, we evaluated the contributions of Candida albicans and its exotoxin candidalysin in alcohol-associated liver disease.MethodsC. albicans and the extent of cell elongation 1 (ECE1) were analyzed in fecal samples from controls, patients with alcohol use disorder and those with alcoholic hepatitis. Mice colonized with different and genetically manipulated C. albicans strains were subjected to the chronic-plus-binge ethanol diet model. Primary hepatocytes were isolated and incubated with candidalysin.ResultsThe percentages of individuals carrying ECE1 were 0%, 4.76% and 30.77% in non-alcoholic controls, patients with alcohol use disorder and patients with alcoholic hepatitis, respectively. Candidalysin exacerbates ethanol-induced liver disease and is associated with increased mortality in mice. Candidalysin enhances ethanol-induced liver disease independently of the β-glucan receptor C-type lectin domain family 7 member A (CLEC7A) on bone marrow-derived cells, and candidalysin does not alter gut barrier function. Candidalysin can damage primary hepatocytes in a dose-dependent manner in vitro and is associated with liver disease severity and mortality in patients with alcoholic hepatitis.ConclusionsCandidalysin is associated with the progression of ethanol-induced liver disease in preclinical models and worse clinical outcomes in patients with alcoholic hepatitis.Lay summaryCandidalysin is a peptide toxin secreted by the commensal gut fungus Candida albicans. Candidalysin enhances alcohol-associated liver disease independently of the β-glucan receptor CLEC7A on bone marrow-derived cells in mice without affecting intestinal permeability. Candidalysin is cytotoxic to primary hepatocytes, indicating a direct role of candidalysin on ethanol-induced liver disease. Candidalysin might be an effective target for therapy in patients with alcohol-associated liver disease.

Project description:Candida-associated denture stomatitis presents as erythema of the palatal mucosa and is caused by biofilms containing the fungus Candida albicans that co-reside with oral bacteria on the denture-fitting surface. This study aimed to assess the effect of several frequently encountered oral bacteria on the expression of C. albicans virulence factors in in vitro polymicrobial biofilms. Biofilms containing C. albicans and selected bacterial species were grown on denture acrylic, and analysed by microscopy and by qPCR for expression of putative virulence genes. Candida albicans-only biofilms showed limited hyphal production. Hyphal development was significantly (P < 0·001) increased when biofilms also contained four species of oral bacteria (Streptococcus sanguinis, Streptococcus gordonii, Actinomyces odontolyticus and Actinomyces viscosus), as was the expression of virulence genes (P < 0·05). Importantly, inclusion of Porphyromonas gingivalis in the biofilm consortium resulted in significant (P < 0·05) inhibition of virulence gene expression and production of hyphae. The in vitro expression of C. albicans virulence factors was modulated in polymicrobial biofilms. The complexity of this modulation was highlighted by the reversal of effects following introduction of a single bacterial species into a biofilm community. SIGNIFICANCE AND IMPACT OF THE STUDY: The impact of individual bacterial species on Candida albicans virulence highlights both the complexity of predicting infection mediated by polymicrobial communities and the potential for management through pro- or prebiotic therapy. The possibility to selectively modulate microbial virulence by addition of, or treatment with pro- or prebiotics avoids the use of conventional antimicrobial compounds, thus reducing the contribution to potential drug resistance. Understanding which bacterial species modulate virulence, and the mechanisms by which this occurs, particularly in biofilms, provides excellent foundations for further research questions, and the potential for novel clinical interventions.

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

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

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