Secretory Aspartyl Proteinases Cause Vaginitis and Can Mediate Vaginitis Caused by Candida albicans in Mice

Vaginal inflammation (vaginitis) is the most common disease caused by the human-pathogenic fungus Candida albicans.Secretory aspartyl proteinases (Sap) are major virulence traits of C. albicans that have been suggested to play a role invaginitis. To dissect the mechanisms by which Sap play this role, Sap2, a dominantly expressed member of the Sap family and aputative constituent of an anti-Candida vaccine, was used. Injection of full-length Sap2 into the mouse vagina caused local neutrophilinflux and accumulation of the inflammasome-dependent interleukin-1beta (IL-1beta) but not of inflammasome-independenttumor necrosis factor alpha. Sap2 could be replaced by other Sap, while no inflammation was induced by the vaccine antigen, theN-terminal-truncated, enzymatically inactive tSap2. Anti-Sap2 antibodies, in particular Fab from a human combinatorial antibodylibrary, inhibited or abolished the inflammatory response, provided the antibodies were able, like the Sap inhibitor PepstatinA, to inhibit Sap enzyme activity. The same antibodies and Pepstatin A also inhibited neutrophil influx and cytokine productionstimulated by C. albicans intravaginal injection, and a mutant strain lacking SAP1, SAP2, and SAP3 was unable to causevaginal inflammation. Sap2 induced expression of activated caspase-1 in murine and human vaginal epithelial cells. Caspase-1inhibition downregulated IL-1beta and IL-18 production by vaginal epithelial cells, and blockade of the IL-1beta receptor stronglyreduced neutrophil influx. Overall, the data suggest that some Sap, particularly Sap2, are proinflammatory proteins in vivo andcan mediate the inflammasome-dependent, acute inflammatory response of vaginal epithelial cells to C. albicans. These findingssupport the notion that vaccine-induced or passively administered anti-Sap antibodies could contribute to control vaginitis.