Role of aspartic proteases in disseminated Candida albicans infection in mice

Abstract

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.

Secreted aspartic proteases of Candida albicans, Candida tropicalis, Candida parapsilosis and Candida lusitaniae

“…A significant dose-dependent protection against a subsequent lethal intranasal dose of C. albicans was observed by pretreatment of neutropenic mice with pepstatin A by intraperitoneal injection. The effect of pepstatin A was comparable to protection obtained with amphotericin B [41]. A reduced depth of invasion of parenchymal organs from the peritoneal cavity and the degree of tissue damage of peritoneal cavity by C. albicans was observed in mice pretreated with pepstatin A [42].…”

Increased tumour necrosis factor-α production, higher mannose receptor activity and ability to killCandidaby concanavalin-A-activated macrophages

“…Although the host immune system is the major factor balancing the transition from commensalism to pathogenicity, several virulence attributes expressed by C. albicans, such as adhesion factors, phenotypic switching, dimorphic behaviour and secretion of hydrolytic enzymes (Fallow et al, 1997;Vargas et al, 2000;Calderone & Fonzi, 2001;Naglik et al, 2003;Romani et al, 2003;Consolaro et al, 2005), might contribute to the persistence of colonization and the development of symptomatic episodes.…”

Low dose of Concanavalin-A enhances innate immune response and prevents liver injury in mice infected withCandida albicans

“…Candida albicans causes several diseases, ranging from mucocutaneous to systemic infection. Various virulence factors contribute to pathogenesis; for example aspartyl proteases and phospholipases play an essential early role in C. albicans dissemination and enhance its ability to colonize deep organs (Fallow et al, 1997;Calderone & Fonzi, 2001), adhesins allow adherence to epithelial and endothelial cells (Naglik et al, 2003), and morphogenesis consists of reversible transitions between unicellular yeast cells and the filamentous growth forms that are present in clinical lesions (Kobayashi & Cutler, 1998;Romani et al, 2003;Consolaro et al, 2005). It has been demonstrated that Th cell reactivity plays a central role in regulating the immune response to C. albicans, Th1 reactivity being responsible for resistance and Th2 reactivity being associated with susceptibility (Nomi et al, 1994;Kaposzta et al, 1998;Romani, 1999).…”