Suppression of type 2 NO-synthase activity in macrophages by Candida albicans

Macrophages (Mphi) are important for the defence against experimental disseminated candidiasis. Nitric oxide (NO) generated by the inducible isoform of NO-synthase (iNOS or NOS2) is thought to contribute to candidacidal effector functions by activated Mphi. In vitro, however, Mphi cannot control the growth and hyphal formation of Candida (C.) albicans. Using mouse peritoneal exudate Mphi stimulated with IFN-gamma and LPS, we examined the effect of C. albicans on NO synthesis, NOS2 enzyme activity and macrophage survival. C. albicans effectively inhibited the production of NO via suppression of total NOS2 protein and enzyme activity. Hyphal formation of C. albicans and direct interaction with host cells was required for maximum inhibition of NO production, whereas non-filamentous C. albicans mutants released soluble products that effected only partial inhibition. Ultimately, Mphi underwent apoptotic cell death after infection with C. albicans wild-type strains capable of hyphal formation, indicated by loss of the mitochondrial membrane potential and onset of chromatin degradation. NO suppression and Mphi killing are potent activities of C. albicans that may augment virulence of C. albicans.