Association of a variable number tandem repeat in the NLRP3 gene in women with susceptibility to RVVC

Jaeger, Martin; Carvalho, Agostinho; Cunha, Cristina; Plantinga, Theo S.; Veerdonk, Frank van de; Puccetti, Matteo; Galosi, Claudia; Joosten, Leo A. B.; Dupont, B.; Kullberg, Bart Jan; Sobel, Jack D.; Romani, Luigina; Netea, Mihai G.

doi:10.1007/s10096-016-2600-5

Cited by 58 publications

(58 citation statements)

References 21 publications

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“…One study measured inflammasome-dependent cytokine production at the mucosal surface and observed enhanced IL-1β levels in the vaginal fluid of RVVC patients compared with healthy controls. Intriguingly, RVVC patients bearing the risk allele demonstrated even higher levels of IL-1β production [84]. In agreement, IL-1Ra levels were lower in recurrent VVC patients.…”

Section: Polymorphism or Expression Changes In Inflammasome-coding Genessupporting

confidence: 60%

“…In agreement, IL-1Ra levels were lower in recurrent VVC patients. Additionally, IL-18 levels were unaltered in the vaginal fluid of patients bearing the risk allele [84]. These studies thus argue that genetic variations in the Nlrp3 gene may influence the progression of VVC and identify IL-1β as a therapeutic target in the management of RVVC.…”

Section: Polymorphism or Expression Changes In Inflammasome-coding Genesmentioning

confidence: 83%

“…The role of inflammasomes during VVC is also corroborated by studies in humans where polymorphism in the gene encoding Nlrp3 is associated with increased incidence of recurrent VVC (RVVC), which is characterized by at least three episodes of infection per year 84, 85. One study measured inflammasome-dependent cytokine production at the mucosal surface and observed enhanced IL-1β levels in the vaginal fluid of RVVC patients compared with healthy controls.…”

Section: Polymorphism or Expression Changes In Inflammasome-coding Genesmentioning

confidence: 85%

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Integrating Inflammasome Signaling in Sexually Transmitted Infections

Lupfer

Anand

2016

Trends in Immunology

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Inflammasomes are cytosolic multiprotein platforms with pivotal roles in infectious diseases. Activation of inflammasomes results in proinflammatory cytokine signaling and pyroptosis. Sexually transmitted infections (STIs) are a major health problem worldwide, yet few studies have probed the impact of inflammasome signaling during these infections. Due to the dearth of appropriate infection models, our current understanding of inflammasomes in STIs is mostly drawn from results obtained in vitro, from distant infection sites, or from related microbial strains that are not sexually transmitted. Understanding how inflammasomes influence the outcome of STIs may lead to the development of novel and effective strategies to control disease and prevent transmission. Here we discuss and highlight the recent progress in this field.

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Section: Polymorphism or Expression Changes In Inflammasome-coding Genessupporting

confidence: 60%

Section: Polymorphism or Expression Changes In Inflammasome-coding Genesmentioning

confidence: 83%

Section: Polymorphism or Expression Changes In Inflammasome-coding Genesmentioning

confidence: 85%

See 1 more Smart Citation

Integrating Inflammasome Signaling in Sexually Transmitted Infections

Lupfer

Anand

2016

Trends in Immunology

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“…The use of NLRP3 Ϫ/Ϫ mice during VVC has demonstrated that neutrophil migration and proinflammatory signaling are reduced in these animals, presumably due to a defect in the ability to recognize and respond to DAMP signals (26,35). Furthermore, a population level genetic study revealed that the 12/9 genotype was significantly associated with high levels of NLRP3 effector cytokines found in the vaginal lavage fluid of women with recurrent VVC (RVVC), suggesting the recognition of DAMP signals is important in disease immunopathogenesis (36). Given that the presence of Candidalysin is sufficient to induce damage at the vaginal mucosa and elicits inflammasome effector responses (i.e., IL-1␤), it is possible that Candidalysin serves as a fungal DAMP capable of inflammasome activation.…”

Section: Figmentioning

confidence: 99%

Candidalysin Drives Epithelial Signaling, Neutrophil Recruitment, and Immunopathology at the Vaginal Mucosa

et al. 2018

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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 1␣ [IL-1␣], IL-1␤, 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.

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“…Surprisingly, SAP overexpression strains did not recruit more neutrophils than their isogenic empty vector control did. We previously identified the pleiotropic innate inflammatory cytokine IL-1␤ as a relevant biomarker of vaginal immunopathology and known effector of inflammasome activa- tion, a crucial host signaling pathway activated during murine VVC (4,6,(22)(23)(24)(25). Importantly, recombinant SAPs have also been demonstrated to activate the inflammasome and to liberate IL-1␤ in the vaginal epithelium (16,26,27).…”

Section: Resultsmentioning

confidence: 99%

Overexpression of Candida albicans Secreted Aspartyl Proteinase 2 or 5 Is Not Sufficient for Exacerbation of Immunopathology in a Murine Model of Vaginitis

et al. 2017

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The secreted aspartyl proteinases of Candida albicans have long been implicated in virulence at the mucosal surface, including contributions to colonization and immunopathogenesis during vulvovaginal candidiasis. In an effort to disentangle hypha-associated virulence factor regulation from morphological transition, the purpose of this study was to determine if overexpression of SAP2 or SAP5 in an efg1Δ/Δ cph1Δ/Δ mutant could restore the capacity to cause immunopathology during murine vaginitis to this avirulent hypofilamentous strain. Two similar yet distinct genetic approaches were used to construct expression vectors to achieve SAP overexpression, and both genetic and functional assays confirmed elevated SAP activity in transformed strains. Similar to previous findings, intravaginal challenge of C57BL/6 mice with hypha-defective strains attained high levels of mucosal colonization but failed to induce robust vaginal immunopathology (neutrophil recruitment, interleukin-1␤ [IL-1␤] secretion, and lactate dehydrogenase release) compared to that with the hyphacompetent control. Moreover, constitutive expression of SAP2 or SAP5 in two distinct sets of such strains did not elicit immunopathological markers at levels above those observed during challenge with isogenic empty vector controls. Therefore, these results suggest that the physiological contributions of SAPs to vaginal immunopathology require hypha formation, other hypha-associated factors, or genetic interaction with EFG1 and/or CPH1 to cause symptomatic infection. Additionally, the outlined expression strategy and strain sets will be useful for decoupling other downstream morphogenetic factors from hyphal growth.KEYWORDS Candida, SAPs, fungal, pathogenesis, vaginitis, virulence factors, vulvovaginal V ulvovaginal candidiasis (VVC), caused by the polymorphic fungal pathogen Candida albicans, is the most prevalent human fungal infection, affecting approximately 75% of women at least once in their lifetime, primarily in their childbearing years (1). Moreover, it is estimated that roughly 5 to 8% of all women suffer from recurrent infection, defined as 3 or more symptomatic episodes per year, requiring continuous antifungal maintenance therapy to prevent infectious relapse (2). Despite its high incidence rate and the significant insight into host response mechanisms that contribute to disease pathogenesis, still relatively little is understood about the fungal virulence factors that govern symptomatic immunopathology.The clinically relevant mouse model of vaginal candidiasis, along with robust approaches to genetically manipulate C. albicans, has been an indispensable tool for

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Association of a variable number tandem repeat in the NLRP3 gene in women with susceptibility to RVVC

Cited by 58 publications

References 21 publications

Integrating Inflammasome Signaling in Sexually Transmitted Infections

Integrating Inflammasome Signaling in Sexually Transmitted Infections

Candidalysin Drives Epithelial Signaling, Neutrophil Recruitment, and Immunopathology at the Vaginal Mucosa

Overexpression of Candida albicans Secreted Aspartyl Proteinase 2 or 5 Is Not Sufficient for Exacerbation of Immunopathology in a Murine Model of Vaginitis

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