Inhibition of C. Albicans Filamentation by a C. Glabrata Biofilm-Produced Factor

Candida species are the fourth leading cause of hospital-acquired bloodstream infections in the United States with an attributable mortality rate of 40-50%. Oral candidiasis is the most common fungal infection encountered in the general dental practice and immunocompromised individuals, including AIDS patients, are particularly susceptible. Candida albicans is the most frequently isolated species in oral thrush patients. C. albicans and C. glabrata are increasingly being co-isolated from fungal lesions in the oral cavity.C. albicans has the ability to undergo a morphological transition from single-celled yeast to hyphal filaments. This transition is required for virulence and plays an important role in the invasion of the oral mucosa as well as biofilm formation. Biofilms are complex microbial communities that are highly resistant to antifungal treatment and also important for the development and persistence of opportunistic yeast infections. Although C. glabrata does not readily form filaments, this species easily forms biofilms. While monospecies C. albicans biofilms have been well-studied, inter-Candida-species signaling interactions that affect filamentation, including filamentation in biofilms, are unknown. My preliminary data indicate that both C. albicans planktonic cells and biofilms are unable to form filaments in the presence of an established C. glabrata biofilm. Inhibition of C. albicans filamentation appears to occur in response to a secreted C. glabrata protein because complete inhibition is observed when C. albicans planktonic cells and biofilms are grown in the supernatant of an independently grown C. glabrata biofilm, the inhibitory activity is lost upon boiling the supernatant, and the inhibitoy factor can be precipitated from the supernatant by ammonium sulfate. Our laboratory has previously shown that constitutive high-level expression of UME6, a key filament-specific transcriptional regulator, is sufficient to generate a nearly complete filamentous population, driv increased biofilm formation and promote virulence. Interestingly, the factor produced by C. glabrata biofilms also completely inhibits C. albicans UME6-driven filamentation in both biofilms and planktonic cultures. Based on these results, my hypothesis is that the inhibitor of C. albicans filamentation produced by C. glabrata biofilms is a secreted factor that acts downstream of the UME6 pathway. In order to test this hypothesis, experiments in this proposal are designed to: 1) determine the identity of the C. glabrata biofilm-produced inhibitor of C. albicans filamentation, 2) determine the role that the C. glabrata biofilm-produced factor plays ininhibiting the virulence properties of a C. albicans UME6 expression strain as well as C. albicans clinical oral isolates. These studies are significant because the will provide important new insight into inter-Candida species signaling interactions that control filamentation of C. albicans, a major human oral fungal pathogen. Because of the important role that filamentation plays in C. albicans oral tissue invasion, biofilm formation, and pathogenesis, these studies are likely to provide information leading to the development of novel and more effective antifungal therapies to treat oral candidiasis. PUBLIC HEALTH RELEVANCE: Candida albicans is the most common cause of fungal infections encountered in the dental practice. C. albicans can adopt a filamentous morphology that is required for virulence and plays an important role in the invasion of the oral mucosa as well as biofilm formation. These studies will provide new and important information about a novel interspecies inhibitor of C. albicans filamentation and are likely to contribute to the development of more effective antifungal therapies to treat oral candidiasis.