A role for secretory aspartyl proteinase of Candida albicans in mouse vaginal inflammation and vaginal candidiasis

We sought for a role of secretory aspartyl proteinase 2, (Sap2), a major virulence trait of Candida albicans, in a murine experimental model of vaginal candidiasis. Injection of enzymatically active, full-length Sap2 into the mouse vagina caused local PMN (neutrophil) influx and accumulation of the inflammasome-dependent interleukin (IL)-1beta but not of inflammasome-independent TNFalpha. No inflammatory response was detected following treatment with a N-terminus-truncated, enzymatically-inactive tSap2. Anti-Sap2 antibodies, in particular Fab from a human combinatorial antibody library inhibited or abolished the inflammatory response, provided they were able, like Pepstatin A, a known Sap inhibitor, to inhibit Sap2 enzyme activity. The same antibodies and Pepstatin A also caused strong inhibition of neutrophil influx and cytokine production early during experimental vaginal infection by Candida albicans. Sap2 induced expression of activated caspase-1 in murine vaginal epithelial cells as well as in a human vaginal epithelial cell line and caspase-1 inhibition down-regulated IL-1beta and IL-18 production by the vaginal epithelial cells. Overall, the data demonstrate that Sap2 is a critical determinant of the acute inflammatory response by the epithelial cells in vaginal candidiasis, and support the notion that vaccine-induced or passively administered anti-Sap antibodies could control vaginal disease.