Virulence of Sporothrix schenckii conidia and yeast cells, and their susceptibility to nitric oxide

The involvement of nitric oxide (NO) in macrophage (M phi) fungicidal activ ity against Sporothrix schenckii, and the relationship between NO susceptib ility and the differential virulence of conidia and yeast cells, were inves tigated. Confirming a previously reported correlation between the length of time in culture and virulence of S. schenckii, conidia isolated from 12-da y mycelial cultures (Ss-12) were less virulent to mice than conidia from 7- day cultures (Ss-7) or yeast cells. Indicative of NO production, infected a nimals showed a significant increase in serum levels of nitrite that was lo wer in mice infected with Ss-12 than in mice infected with Ss-7 or yeast. S timulation of murine M phi with interferon-gamma (IFN-gamma) induced NO pro duction and inhibition of fungal growth. The cytotoxic activity of M phi ag ainst Ss-12 was significantly greater than against Ss-7 or yeast cells, the highly virulent fungal forms. The addition of NO synthase inhibitors abrog ated M phi cytotoxic activity against all fungal forms. The phagocytic acti vity of M phi against Ss-7 was significantly lower than against Ss-12 or ye ast cells. Although the ingestion of fungal cells triggered the oxidative b urst in M phi, the fungicidal activity was not altered in the presence of s uperoxide dismutase (SOD) and catalase. In addition, Ss-12 and yeast cells were more susceptible than Ss-7 to the direct fungicidal activity of the NO donors S-nitroso-N-acetyl-DL-penicillamine (SNAP), S-nitrosoglutathione (G SNO) and 3-morpholinosydnonimine (SIN-1). The results of this study indicat e that NO is a key cytotoxic mediator involved in the murine M phi defence against S. schenckii, and that the virulence of Ss-7, Ss-12 and yeast cells may be related to a differential susceptibility to NO.