Role of Aspartic Proteases in Disseminated Candida albicans Infection in Mice

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 dis-semination. Pretreatment of neutropenic mice with the aspartic protease inhibitor pepstatin A by intraperi-toneal 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 weight21 prior to challenge and on days 1 to 4 postchallenge resulted in 100 % survival at day 15 post-challenge, 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 kg21. 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. Candida albicans and Candida tropicalis account for more than 80 % of fungi isolated from patients with invasive candi