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

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 n...

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Main Authors:	Bruno, Vincent M., Shetty, Amol C., Yano, Junko, Fidel, Paul L., Noverr, Mairi C., Peters, Brian M.
Format:	Online
Language:	English
Published:	American Society of Microbiology 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453569/

id	pubmed-4453569
recordtype	oai_dc
spelling	pubmed-44535692015-06-03 Transcriptomic Analysis of Vulvovaginal Candidiasis Identifies a Role for the NLRP3 Inflammasome Bruno, Vincent M. Shetty, Amol C. Yano, Junko Fidel, Paul L. Noverr, Mairi C. Peters, Brian M. Research Article 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. American Society of Microbiology 2015-04-21 /pmc/articles/PMC4453569/ /pubmed/25900651 http://dx.doi.org/10.1128/mBio.00182-15 Text en Copyright © 2015 Bruno et al. http://creativecommons.org/licenses/by-nc-sa/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license (http://creativecommons.org/licenses/by-nc-sa/3.0/) , which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Bruno, Vincent M. Shetty, Amol C. Yano, Junko Fidel, Paul L. Noverr, Mairi C. Peters, Brian M.
spellingShingle	Bruno, Vincent M. Shetty, Amol C. Yano, Junko Fidel, Paul L. Noverr, Mairi C. Peters, Brian M. Transcriptomic Analysis of Vulvovaginal Candidiasis Identifies a Role for the NLRP3 Inflammasome
author_facet	Bruno, Vincent M. Shetty, Amol C. Yano, Junko Fidel, Paul L. Noverr, Mairi C. Peters, Brian M.
author_sort	Bruno, Vincent M.
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
description	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.
publisher	American Society of Microbiology
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4453569/
_version_	1613231150200782848

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

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