Abstract
Vulvovaginal candidiasis (VVC) caused by Candida albicans affects a significant number of women during their reproductive ages. Clinical observations revealed that a robust vaginal polymorphonuclear neutrophil (PMN) migration occurs in susceptible women, promoting pathological inflammation without affecting fungal burden. Evidence to date in the mouse model suggests that a similar acute PMN migration into the vagina is mediated by chemotactic S100A8 and S100A9 alarmins produced by vaginal epithelial cells in response to Candida. Based on the putative role for the Th17 response in mucosal candidiasis as well as S100 alarmin induction, this study aimed to determine whether the Th17 pathway plays a role in the S100 alarmin-mediated acute inflammation during VVC using the experimental mouse model. For this, IL-23p19−/−, IL-17RA−/− and IL-22−/− mice were intravaginally inoculated with Candida, and vaginal lavage fluids were evaluated for fungal burden, PMN infiltration, the presence of S100 alarmins and inflammatory cytokines and chemokines. Compared to wild-type mice, the cytokine-deficient mice showed comparative levels of vaginal fungal burden and PMN infiltration following inoculation. Likewise, inoculated mice of all strains with substantial PMN infiltration exhibited elevated levels of vaginal S100 alarmins in both vaginal epithelia and secretions in the vaginal lumen. Finally, cytokine analyses of vaginal lavage fluid from inoculated mice revealed equivalent expression profiles irrespective of the Th17 cytokine status or PMN response. These data suggest that the vaginal S100 alarmin response to Candida does not require the cells or cytokines of the Th17 lineage, and therefore, the immunopathogenic inflammatory response during VVC occurs independently of the Th17-pathway.
Highlights
Vulvovaginal candidiasis (VVC), caused by Candida species, is an opportunistic fungal infection that affects approximately 75% of healthy women of childbearing age [1]
polymorphonuclear neutrophil (PMN) chemotactic activity of vaginal lavage fluid was dramatically reduced following antibody neutralization of S100A8 in vitro. These findings suggested that in the mouse model, epithelial cellderived S100A8 alarmin mediates the acute PMN response that leads to the pathological inflammation associated with vaginitis
To evaluate whether Candida is able to establish vaginal colonization in mice deficient in Th17 lineage, estrogenized IL23p192/2, IL-222/2, IL-17RA2/2 and wild-type mice were inoculated with Candida, and vaginal lavage fluids were collected on day 4 and 7 post-inoculation and evaluated for fungal burden
Summary
Vulvovaginal candidiasis (VVC), caused by Candida species, is an opportunistic fungal infection that affects approximately 75% of healthy women of childbearing age [1]. Results from a human live challenge study revealed that protection occurs in the absence of any inflammatory response, whereas symptomatic infection is associated with a vaginal cellular infiltrate consisting exclusively of polymorphonuclear neutrophils (PMNs) [4]. We recently reported evidence implicating that the PMN migration is mediated by chemotactic S100A8 and S100A9 alarmins produced by vaginal epithelial cells in response to Candida [5]. PMN chemotactic activity of vaginal lavage fluid was dramatically reduced following antibody neutralization of S100A8 in vitro. These findings suggested that in the mouse model, epithelial cellderived S100A8 alarmin mediates the acute PMN response that leads to the pathological inflammation associated with vaginitis
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