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Candidalysin Drives Epithelial Signaling, Neutrophil Recruitment, and Immunopathology at the Vaginal Mucosa.
Infect Immun. 2018 02; 86(2)II

Abstract

Unlike other forms of candidiasis, vulvovaginal candidiasis, caused primarily by the fungal pathogen Candida albicans, 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 C. albicans hyphae during invasion, drives epithelial damage, immune activation, and phagocyte attraction. Therefore, we hypothesized that Candidalysin is crucial for vulvovaginal candidiasis immunopathology. Anti-Candida 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 C. albicans-infected human vaginal epithelium in vitro 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 C. albicans 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 C. albicans vaginitis.

Authors+Show Affiliations

King's College London, Division of Mucosal and Salivary Biology, London, United Kingdom.University of Tennessee Health Science Center, Department of Clinical Pharmacy, Memphis, Tennessee, USA.King's College London, Division of Mucosal and Salivary Biology, London, United Kingdom. King's College London, Centre for Host-Microbiome Interactions, London, United Kingdom.King's College London, Centre for Host-Microbiome Interactions, London, United Kingdom.University of Tennessee Health Science Center, Department of Clinical Pharmacy, Memphis, Tennessee, USA.King's College London, Division of Mucosal and Salivary Biology, London, United Kingdom.University of Tennessee Health Science Center, Department of Clinical Pharmacy, Memphis, Tennessee, USA.Department of Microbial Pathogenicity Mechanisms, Hans Knöll Institute, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany. Friedrich-Schiller-University Jena, Jena, Germany.King's College London, Division of Mucosal and Salivary Biology, London, United Kingdom julian.naglik@kcl.ac.uk brian.peters@uthsc.edu.University of Tennessee Health Science Center, Department of Clinical Pharmacy, Memphis, Tennessee, USA julian.naglik@kcl.ac.uk brian.peters@uthsc.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29109176

Citation

Richardson, Jonathan P., et al. "Candidalysin Drives Epithelial Signaling, Neutrophil Recruitment, and Immunopathology at the Vaginal Mucosa." Infection and Immunity, vol. 86, no. 2, 2018.
Richardson JP, Willems HME, Moyes DL, et al. Candidalysin Drives Epithelial Signaling, Neutrophil Recruitment, and Immunopathology at the Vaginal Mucosa. Infect Immun. 2018;86(2).
Richardson, J. P., Willems, H. M. E., Moyes, D. L., Shoaie, S., Barker, K. S., Tan, S. L., Palmer, G. E., Hube, B., Naglik, J. R., & Peters, B. M. (2018). Candidalysin Drives Epithelial Signaling, Neutrophil Recruitment, and Immunopathology at the Vaginal Mucosa. Infection and Immunity, 86(2). https://doi.org/10.1128/IAI.00645-17
Richardson JP, et al. Candidalysin Drives Epithelial Signaling, Neutrophil Recruitment, and Immunopathology at the Vaginal Mucosa. Infect Immun. 2018;86(2) PubMed PMID: 29109176.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Candidalysin Drives Epithelial Signaling, Neutrophil Recruitment, and Immunopathology at the Vaginal Mucosa. AU - Richardson,Jonathan P, AU - Willems,Hubertine M E, AU - Moyes,David L, AU - Shoaie,Saeed, AU - Barker,Katherine S, AU - Tan,Shir Lynn, AU - Palmer,Glen E, AU - Hube,Bernhard, AU - Naglik,Julian R, AU - Peters,Brian M, Y1 - 2018/01/22/ PY - 2017/09/07/received PY - 2017/11/03/accepted PY - 2017/11/8/pubmed PY - 2019/4/13/medline PY - 2017/11/8/entrez KW - Candida KW - Candidalysin KW - epithelial cells KW - immunopathogenesis KW - mucosal immunity KW - mucosal pathogens KW - mycology KW - vaginitis KW - vulvovaginal JF - Infection and immunity JO - Infect Immun VL - 86 IS - 2 N2 - Unlike other forms of candidiasis, vulvovaginal candidiasis, caused primarily by the fungal pathogen Candida albicans, 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 C. albicans hyphae during invasion, drives epithelial damage, immune activation, and phagocyte attraction. Therefore, we hypothesized that Candidalysin is crucial for vulvovaginal candidiasis immunopathology. Anti-Candida 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 C. albicans-infected human vaginal epithelium in vitro 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 C. albicans 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 C. albicans vaginitis. SN - 1098-5522 UR - https://www.unboundmedicine.com/medline/citation/29109176/Candidalysin_Drives_Epithelial_Signaling_Neutrophil_Recruitment_and_Immunopathology_at_the_Vaginal_Mucosa_ L2 - http://iai.asm.org/cgi/pmidlookup?view=long&pmid=29109176 DB - PRIME DP - Unbound Medicine ER -