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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Veröffentlicht in:	Infection and immunity Jg. 86; H. 2
Hauptverfasser:	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
Sprache:	Englisch
Veröffentlicht:	United States 01.02.2018
Schlagworte:	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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Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1098-5522 1098-5522
DOI:	10.1128/IAI.00645-17