Local albumin excess exacerbates Candida albicans-induced inflammasome activation underlying the immunopathology of vulvovaginal candidiasis.

Abstract

Vulvovaginal candidiasis (VVC) is a mucosal yeast infection where symptoms are driven by inflammatory responses. The onset of VVC is instigated by the yeast Candida albicans, but the underlying causes of disease-driving hyperinflammation remains incompletely resolved. We found that vaginal albumin concentrations are higher in women with recurrent VVC and during VVC in mice. These albumin levels correlated with inflammatory cytokines in vaginal lavages. While the abundance of this serum protein in the vagina can represent a hallmark of inflammation-induced vascular permeability, we reveal molecular mechanisms by which albumin also drives inflammation. It increased NLRP3 inflammasome activation in human macrophages elicited by C. albicans. Albumin induced fungal adaptations that increased resistance to macrophage-mediated clearance. Further it increased the expression of fungal secreted aspartic protease 1, which we identified as the effector driving inflammasome activation. Moreover, neutrophils show impaired effectivity in clearing C. albicans in presence of albumin. Collectively, vaginal albumin may not only be a consequence of inflammation of the vaginal mucosa, but also can drive hyperinflammatory responses that underlie immunopathology in VVC. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC="FIGDIR/small/700771v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@f13fd5org.highwire.dtl.DTLVardef@95e58aorg.highwire.dtl.DTLVardef@11104dforg.highwire.dtl.DTLVardef@56e9be_HPS_FORMAT_FIGEXP M_FIG C_FIG