Candidalysin Drives Epithelial Signaling, Neutrophil Recruitment, and Immunopathology at the Vaginal Mucosa

Unlike other forms of candidiasis, vulvovaginal candidiasis, caused primarily by the fungal pathogen , is a disease of immunocompetent and otherwise healthy women. Despite its prevalence, the fungal factors responsible for initiating symptomatic infection remain poorly understood. One of the hallmar...

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Bibliographic Details
Published in:Infection and immunity Vol. 86; no. 2
Main Authors: Richardson, Jonathan P, Willems, Hubertine M E, Moyes, David L, Shoaie, Saeed, Barker, Katherine S, Tan, Shir Lynn, Palmer, Glen E, Hube, Bernhard, Naglik, Julian R, Peters, Brian M
Format: Journal Article
Language:English
Published: United States 01.02.2018
Subjects:
Animals
Candida albicans - pathogenicity
Candidiasis, Vulvovaginal - immunology
Candidiasis, Vulvovaginal - metabolism
Cytokines - metabolism
Epithelial Cells - metabolism
Epithelial Cells - microbiology
Female
Fungal Proteins - metabolism
Fungal Proteins - pharmacology
Humans
Mice
Mucous Membrane - microbiology
Mucous Membrane - pathology
Neutrophil Infiltration - immunology
Signal Transduction
Vagina - immunology
Vagina - metabolism
Vagina - microbiology
Virulence Factors
Candidalysin
immunopathogenesis
vulvovaginal
Candida
mucosal pathogens
epithelial cells
mycology
vaginitis
mucosal immunity
ISSN:1098-5522, 1098-5522
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Summary:Unlike other forms of candidiasis, vulvovaginal candidiasis, caused primarily by the fungal pathogen , is a disease of immunocompetent and otherwise healthy women. Despite its prevalence, the fungal factors responsible for initiating symptomatic infection remain poorly understood. One of the hallmarks of vaginal candidiasis is the robust recruitment of neutrophils to the site of infection, which seemingly do not clear the fungus, but rather exacerbate disease symptomatology. Candidalysin, a newly discovered peptide toxin secreted by hyphae during invasion, drives epithelial damage, immune activation, and phagocyte attraction. Therefore, we hypothesized that Candidalysin is crucial for vulvovaginal candidiasis immunopathology. Anti- immune responses are anatomical-site specific, as effective gastrointestinal, oral, and vaginal immunities are uniquely compartmentalized. Thus, we aimed to identify the immunopathologic role of Candidalysin and downstream signaling events at the vaginal mucosa. Microarray analysis of -infected human vaginal epithelium revealed signaling pathways involved in epithelial damage responses, barrier repair, and leukocyte activation. Moreover, treatment of A431 vaginal epithelial cells with Candidalysin induced dose-dependent proinflammatory cytokine responses (including interleukin 1α [IL-1α], IL-1β, and IL-8), damage, and activation of c-Fos and mitogen-activated protein kinase (MAPK) signaling, consistent with fungal challenge. Mice intravaginally challenged with strains deficient in Candidalysin exhibited no differences in colonization compared to isogenic controls. However, significant decreases in neutrophil recruitment, damage, and proinflammatory cytokine expression were observed with these strains. Our findings demonstrate that Candidalysin is a key hypha-associated virulence determinant responsible for the immunopathogenesis of vaginitis.
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ISSN:1098-5522
1098-5522
DOI:10.1128/IAI.00645-17