A murine model of disseminated candidiasis involving intranasal challenge with Candida albicans was developed and used to explore the role of C. albicans aspartic proteases as virulence factors during early dissemination. Pretreatment of neutropenic mice with the aspartic protease inhibitor pepstatin A by intraperitoneal injection afforded strong dose-dependent protection against a subsequent lethal intranasal dose of an aspartic protease-producing strain (ATCC 32354) of C. albicans. Administration of 0.6 mg of pepstatin A kg of body weight(-1) prior to challenge and on days 1 to 4 postchallenge resulted in 100 survival at day 15 postchallenge, whereas 100 of animals receiving saline had died by day 6. This effect was comparable to the dose-dependent protection obtained with amphotericin B, which resulted in 100 survival when administered at 0.1 mg kg(-1). The reduction in mortality afforded by pepstatin A correlated with its dose-dependent blockade of C. albicans numbers in the lungs, liver, and kidneys. By sharp contrast, no protection by pepstatin A was observed in mice challenged intravenously, and protection was markedly attenuated in mice given pepstatin A after intranasal challenge only. These data show the utility of pepstatin A in the prophylaxis of disseminated Candida infections and suggest that Candida aspartic proteases play an essential role early in dissemination.
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