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

Vincent M. Bruno, Amol C. Shetty, Junko Yano, Paul L. Fidel, Mairi C. Noverr, Brian Peters

Research output: Contribution to journalArticle

49 Citations (Scopus)

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-1ß (IL-1ß) (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-1ß 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, ßSAP4–6 triple and ßSAP5 single mutants induced significantly less PMN influx and IL-1ß 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.

Original languageEnglish (US)
Pages (from-to)1-15
Number of pages15
JournalmBio
Volume6
Issue number2
DOIs
StatePublished - Jan 1 2015

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Vulvovaginal Candidiasis
Inflammasomes
Candida albicans
Interleukin-1
Aspartic Acid Proteases
Hyphae
Transcriptome
Vaginal Douching
Intravaginal Administration
RNA Sequence Analysis
Glyburide
Genes
Virulence
Neutrophils
RNA
Cytokines
Therapeutics
Infection

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Virology

Cite this

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.

In: mBio, Vol. 6, No. 2, 01.01.2015, p. 1-15.

Research output: Contribution to journalArticle

Bruno, Vincent M. ; Shetty, Amol C. ; Yano, Junko ; Fidel, Paul L. ; Noverr, Mairi C. ; Peters, Brian. / Transcriptomic Analysis of Vulvovaginal Candidiasis Identifies a Role for the NLRP3 Inflammasome. In: mBio. 2015 ; Vol. 6, No. 2. pp. 1-15.
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