NLRP3 inflammasome is a key player in human vulvovaginal disease caused by Candida albicans

Roselletti, Elena; Perito, Stefano; Gabrielli, Elena; Mencacci, Antonella; Pericolini, Eva; Sabbatini, Samuele; Cassone, Antonio; Vecchiarelli, Anna

doi:10.1038/s41598-017-17649-8

Cited by 48 publications

(77 citation statements)

References 43 publications

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“…This event, in turn, induces elevated infiltration levels of the same mediators, establishing a positive feedback mechanism loop that results in a hyperinflammatory state [95]. Notably, the same pattern of inflammatory mediators has been reported in VVC patients, with little-to-no expression in asymptomatic colonized carriers and healthy women, providing evidence that NLRP3 is a hallmark of symptomatic immunopathology in humans [118]. Hence, VVC/RVVC might result from an overly aggressive innate reaction by PMNs, rather than an impaired adaptive immune response (Figure 2) [88,119].…”

Section: Immunology: Rvvc As An Autoinflammatory Diseasementioning

confidence: 55%

Recurrent Vulvovaginal Candidiasis: An Immunological Perspective

et al. 2020

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Vulvovaginal candidiasis (VVC) is a widespread vaginal infection primarily caused by Candida albicans. VVC affects up to 75% of women of childbearing age once in their life, and up to 9% of women in different populations experience more than three episodes per year, which is defined as recurrent vulvovaginal candidiasis (RVVC). RVVC results in diminished quality of life as well as increased associated healthcare costs. For a long time, VVC has been considered the outcome of inadequate host defenses against Candida colonization, as in the case of primary immunodeficiencies associated with persistent fungal infections and insufficient clearance. Intensive research in recent decades has led to a new hypothesis that points toward a local mucosal overreaction of the immune system rather than a defective host response to Candida colonization. This review provides an overview of the current understanding of the host immune response in VVC pathogenesis and suggests that a tightly regulated fungus–host–microbiota interplay might exert a protective role against recurrent Candida infections.

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Section: Immunology: Rvvc As An Autoinflammatory Diseasementioning

confidence: 55%

Recurrent Vulvovaginal Candidiasis: An Immunological Perspective

et al. 2020

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“…NAC species do not effectively elicit NLRP3 inflammasome-dependent IL-1␤ release. Since we and others have previously demonstrated an important role for the NLRP3 inflammasome in governing early neutrophil recruitment and inflammatory cytokine signaling (including IL-1␤) during VVC, we wished to determine the relative capacities of the Candida species to stimulate NLRP3-dependent IL-1␤ release (7,8,31). In order to assess comparative pathogenicity, we challenged both wild-type (WT) and NLRP3 Ϫ/Ϫ differentiated THP-1-derived human macrophages with equivalent amounts…”

Section: Resultsmentioning

confidence: 99%

Comparative Analysis of the Capacity of the Candida Species To Elicit Vaginal Immunopathology

et al. 2018

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The human fungal pathogen is the major etiological agent of vulvovaginal candidiasis (VVC). Despite this fact, other non- (NAC) species have frequently been reported as well. Despite their presence in the vaginal environment, little is known about their capacity to elicit immune responses classically associated with -mediated immunopathology, including neutrophil recruitment and pro-inflammatory cytokine signaling. Therefore, using a combination of in vitro and in vivo approaches, we undertook a comparative analysis to determine whether a representative panel of NAC species could colonize, induce immunopathological markers, or cause damage at the vaginal mucosa. Using a murine model of VVC, was found to induce robust immunopathology (neutrophils, IL-1β) and elicit mucosal damage. However, all NAC species tested (including ,, ,, ,) induced significantly less damage and neutrophil recruitment, despite achieving similar early colonization levels as These results largely correlated with notable lack of the NAC species ( and included) to form hyphae both in vitro and in vivo. Furthermore, both and induced significantly less expression of the gene encoding for Candidalysin, a key fungal virulence determinant driving VVC immunopathology. In order to determine the relative capacity of these species to elicit inflammasome-dependent IL-1β release, both WT and NLRP3-/- THP-1 cells were challenged in vitro. While most species tested elicited only modest amounts of IL-1β, challenge with led to significantly elevated levels that were largely NLRP3-dependent. Collectively, our findings demonstrate that although NAC species are increasingly reported as causative agents of VVC, appears to be exceedingly vaginopathogenic, exhibiting robust immunopathology, hypha formation and Candidalysin expression. Thus, this study provides mechanistic insight as to why is overwhelmingly the major pathogen reported during VVC.

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“…Around 100 μL of the sample was examined under a light microscope (Olympus, Milan, Italy) to evaluate the presence of neutrophils (PMNs) and EC exfoliation. The numbers of PMNs and ECs were counted in four fields at ×400 magnification and expressed as the average number of PMNs or ECs/field, as previously described 10,19,27 .…”

Section: Methods Participantsmentioning

confidence: 99%

Apoptosis of vaginal epithelial cells in clinical samples from women with diagnosed bacterial vaginosis

Roselletti

Sabbatini

Perito

et al. 2020

Sci Rep

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Bacterial vaginosis (BV) is one of the most common vaginal infections among women of childbearing age. Gardnerella vaginalis (G. vaginalis) is a keystone microorganism present in more than 95% of all BV cases. The first step of the infection process in BV is mediated by interaction of microorganisms with epithelial cells (ECs). However, the role of these cells in BV pathogenesis is largely unknown. The present study aimed to investigate the vaginal EC response during BV. Twenty healthy women and 34 women with BV were enrolled in this study. The number of ECs in the vaginal swab was counted and analyzed for intracellular signals and apoptosis by flow cytometry. Cell damage was evaluated by lactate dehydrogenase assay. Compared to that in healthy donors, the percentage of exfoliated vaginal ECs was increased in women with BV, and an absence of neutrophils was observed in both groups. Activation signals, such as p-IκBα and c-Fos were unmodulated in the vaginal ECs of women with BV. Moreover, EC damage and apoptosis were significantly increased in patients with BV. Apoptosis was related to caspase-3 activation and the presence of G. vaginalis. This study provides the first evidence of a direct involvement of G. vaginalis in the apoptotic process of vaginal ECs during BV. This effect was mediated by caspase-3 activation, and G. vaginalis appeared to be one of causes for inducing EC apoptosis in BV. Hence, our findings suggest a possible explanation for the increased exfoliation of ECs in the vagina during BV.

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NLRP3 inflammasome is a key player in human vulvovaginal disease caused by Candida albicans

Cited by 48 publications

References 43 publications

Recurrent Vulvovaginal Candidiasis: An Immunological Perspective

Recurrent Vulvovaginal Candidiasis: An Immunological Perspective

Comparative Analysis of the Capacity of the Candida Species To Elicit Vaginal Immunopathology

Apoptosis of vaginal epithelial cells in clinical samples from women with diagnosed bacterial vaginosis

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