Secretory aspartyl-proteinases of Candida albicans contribute to severe inflammation observed in the course of vaginal candidiasis

Candidiasis remains a notable health problem in subjects with underlying disease and several risk factors (diabetes, deep surgery, HIV infection, genetic predisposition and others) because of elevated mortality (candidemia and deep-seated infections), chronicity and recurrences in high prevalence clinical settings (oral and vaginal candidiasis), perceived increased risk of drug-resistance and lack of specific preventive measures such as vaccines. Within this framework, the high capacity of the major agent of candidiasis, Candida albicans (C. albicans), to express virulence factors causing inflammation and deceiving host immune system is remarkable and should constitute an important new concept/target to fight candidiasis by new tools providing an alternative or integration to the existing drugs. Secretory aspartyl-proteinases of C. albicans (SAP) are dominant virulence attributes of C. albicans and are considered to play an important role in the pathogenicity of this fungus. Using purified, enzymatically active, recombinant SAP, we demonstrated that SAP, including SAP2 and SAP6, are strong activators of NLRP3 inflammasome both in monocytes and epithelial cells. This occurs via NLRP3 and caspase-1 activation which cleaves pro-IL1\uf062 into secreted bioactive IL-1\uf062. The demonstration that proinflammatory cytokine production is induced by SAP through inflammasome activation implies new role for these virulence factors related to their structural features. Particularly, inflammasome activation may contribute to severe inflammation and recruitment of neutrophils, a scenario characteristic in the pathology of vaginal candidiasis, during SAP production or exposure in the vaginal environment. Our data strongly suggest that SAP2 production may contribute to the excessive inflammatory response observed during C. albicans infections, which may be the hallmark of at least some Candida pathologies