Transcriptomic Analysis of Vulvovaginal Candidiasis Identifies a Role for the NLRP3 Inflammasome

ABSTRACT Treatment of vulvovaginal candidiasis (VVC), caused most frequently by Candida albicans, represents a significant unmet clinical need. C. albicans, as both a commensal and a pathogenic organism, has a complex and poorly understood interaction with the vaginal environment. Understanding the...

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Autores principales:	Vincent M. Bruno, Amol C. Shetty, Junko Yano, Paul L. Fidel, Mairi C. Noverr, Brian M. Peters
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/fb54e312e36a4b62aba8ccee5f82be11
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spelling	oai:doaj.org-article:fb54e312e36a4b62aba8ccee5f82be112021-11-15T15:41:33ZTranscriptomic Analysis of Vulvovaginal Candidiasis Identifies a Role for the NLRP3 Inflammasome10.1128/mBio.00182-152150-7511https://doaj.org/article/fb54e312e36a4b62aba8ccee5f82be112015-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00182-15https://doaj.org/toc/2150-7511ABSTRACT Treatment of vulvovaginal candidiasis (VVC), caused most frequently by Candida albicans, represents a significant unmet clinical need. C. albicans, as both a commensal and a pathogenic organism, has a complex and poorly understood interaction with the vaginal environment. Understanding the complex nature of this relationship is necessary for the development of desperately needed therapies to treat symptomatic infection. Using transcriptome sequencing (RNA-seq), we characterized the early murine vaginal and fungal transcriptomes of the organism during VVC. Network analysis of host genes that were differentially expressed between infected and naive mice predicted the activation or repression of several signaling pathways that have not been previously associated with VVC, including NLRP3 inflammasome activation. Intravaginal challenge of Nlrp3−/− mice with C. albicans demonstrated severely reduced levels of polymorphonuclear leukocytes (PMNs), alarmins, and inflammatory cytokines, including interleukin-1β (IL-1β) (the hallmarks of VVC immunopathogenesis) in vaginal lavage fluid. Intravaginal administration of wild-type (WT) mice with glyburide, a potent inhibitor of the NLRP3 inflammasome, reduced PMN infiltration and IL-1β to levels comparable to those observed in Nlrp3−/− mice. Furthermore, RNA-seq analysis of C. albicans genes indicated robust expression of hypha-associated secreted aspartyl proteinases 4, 5, and 6 (SAP4–6), which are known inflammasome activators. Despite colonization similar to that of the WT strain, ΔSAP4–6 triple and ΔSAP5 single mutants induced significantly less PMN influx and IL-1β during intravaginal challenge. Our findings demonstrate a novel role for the inflammasome in the immunopathogenesis of VVC and implicate the hypha-associated SAPs as major C. albicans virulence determinants during vulvovaginal candidiasis. IMPORTANCE Vaginitis, most commonly caused by the fungus Candida albicans, results in significant quality-of-life issues for all women of reproductive age. Recent efforts have suggested that vaginitis results from an immunopathological response governed by host innate immunity, although an explanatory mechanism has remained undefined. Using comprehensive genomic, immunological, and pharmacological approaches, we have elucidated the NLRP3 inflammasome as a crucial molecular mechanism contributing to host immunopathology. We have also demonstrated that C. albicans hypha-associated secreted aspartyl proteinases (SAP4–6 and SAP5, more specifically) contribute to disease immunopathology. Ultimately, this study enhances our understanding of the complex interplay between host and fungus at the vaginal mucosa and provides proof-of-principle evidence for therapeutic targeting of inflammasomes for symptomatic vulvovaginal candidiasis.Vincent M. BrunoAmol C. ShettyJunko YanoPaul L. FidelMairi C. NoverrBrian M. PetersAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 2 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Vincent M. Bruno Amol C. Shetty Junko Yano Paul L. Fidel Mairi C. Noverr Brian M. Peters Transcriptomic Analysis of Vulvovaginal Candidiasis Identifies a Role for the NLRP3 Inflammasome
description	ABSTRACT Treatment of vulvovaginal candidiasis (VVC), caused most frequently by Candida albicans, represents a significant unmet clinical need. C. albicans, as both a commensal and a pathogenic organism, has a complex and poorly understood interaction with the vaginal environment. Understanding the complex nature of this relationship is necessary for the development of desperately needed therapies to treat symptomatic infection. Using transcriptome sequencing (RNA-seq), we characterized the early murine vaginal and fungal transcriptomes of the organism during VVC. Network analysis of host genes that were differentially expressed between infected and naive mice predicted the activation or repression of several signaling pathways that have not been previously associated with VVC, including NLRP3 inflammasome activation. Intravaginal challenge of Nlrp3−/− mice with C. albicans demonstrated severely reduced levels of polymorphonuclear leukocytes (PMNs), alarmins, and inflammatory cytokines, including interleukin-1β (IL-1β) (the hallmarks of VVC immunopathogenesis) in vaginal lavage fluid. Intravaginal administration of wild-type (WT) mice with glyburide, a potent inhibitor of the NLRP3 inflammasome, reduced PMN infiltration and IL-1β to levels comparable to those observed in Nlrp3−/− mice. Furthermore, RNA-seq analysis of C. albicans genes indicated robust expression of hypha-associated secreted aspartyl proteinases 4, 5, and 6 (SAP4–6), which are known inflammasome activators. Despite colonization similar to that of the WT strain, ΔSAP4–6 triple and ΔSAP5 single mutants induced significantly less PMN influx and IL-1β during intravaginal challenge. Our findings demonstrate a novel role for the inflammasome in the immunopathogenesis of VVC and implicate the hypha-associated SAPs as major C. albicans virulence determinants during vulvovaginal candidiasis. IMPORTANCE Vaginitis, most commonly caused by the fungus Candida albicans, results in significant quality-of-life issues for all women of reproductive age. Recent efforts have suggested that vaginitis results from an immunopathological response governed by host innate immunity, although an explanatory mechanism has remained undefined. Using comprehensive genomic, immunological, and pharmacological approaches, we have elucidated the NLRP3 inflammasome as a crucial molecular mechanism contributing to host immunopathology. We have also demonstrated that C. albicans hypha-associated secreted aspartyl proteinases (SAP4–6 and SAP5, more specifically) contribute to disease immunopathology. Ultimately, this study enhances our understanding of the complex interplay between host and fungus at the vaginal mucosa and provides proof-of-principle evidence for therapeutic targeting of inflammasomes for symptomatic vulvovaginal candidiasis.
format	article
author	Vincent M. Bruno Amol C. Shetty Junko Yano Paul L. Fidel Mairi C. Noverr Brian M. Peters
author_facet	Vincent M. Bruno Amol C. Shetty Junko Yano Paul L. Fidel Mairi C. Noverr Brian M. Peters
author_sort	Vincent M. Bruno
title	Transcriptomic Analysis of Vulvovaginal Candidiasis Identifies a Role for the NLRP3 Inflammasome
title_short	Transcriptomic Analysis of Vulvovaginal Candidiasis Identifies a Role for the NLRP3 Inflammasome
title_full	Transcriptomic Analysis of Vulvovaginal Candidiasis Identifies a Role for the NLRP3 Inflammasome
title_fullStr	Transcriptomic Analysis of Vulvovaginal Candidiasis Identifies a Role for the NLRP3 Inflammasome
title_full_unstemmed	Transcriptomic Analysis of Vulvovaginal Candidiasis Identifies a Role for the NLRP3 Inflammasome
title_sort	transcriptomic analysis of vulvovaginal candidiasis identifies a role for the nlrp3 inflammasome
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/fb54e312e36a4b62aba8ccee5f82be11
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Transcriptomic Analysis of Vulvovaginal Candidiasis Identifies a Role for the NLRP3 Inflammasome

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