Control of Candida albicans Filamentous Growth and Virulence

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Candida albicans is the major human fungal pathogen responsible for a wide variety of systemic and mucosal infections. Immunocompromised individuals such as AIDS patients, organ transplant recipients, cancer patients undergoing chemotherapy and recipients of artificial joints and prosthetic devices are particularly susceptible to C. albicans infections. C. albicans is known to undergo a morphological transition from blastospores (single round budding yeast cells) to pseudohyphal and hyphal filaments (elongated cells attached end-to-end). The ability to undergo this transition is required for virulence. Our long-term goal is to determine the mechanisms by which C. albicans controls morphology and virulence in response to specific host environmental cues. In order to achieve this goal we have identified several key transcriptional regulators that control C. albicans filamentation as well as expression of the C. albicans filamentous growth program. We have recently shown that expression levels of one of these regulators, UME6 (encoding a novel filament-specific protein), are sufficient to determine C. albicans morphological form, drive hyphal filament extension and confer enhanced virulence in a mouse model of systemic candidiasis; extension of hyphal filaments is known to play a key role in a variety of virulence-related processes. A second regulator, Nrg1, functions as a key repressor of filamentation and is down-regulated in response to serum and 37¿C (one of the strongest filament-inducing conditions). Several lines of evidence suggest that Nrg1 and Ume6 function together to control filamentous growth and virulence in response to a variety of specific host environmetal cues and signals. In order to address this hypothesis we will carry out the following specific aims: 1) determine the mechanism by which Nrg1 and Ume6 control filamentous growth as well as expression of the C. albicans filamentous growth program, 2) determine the extent to which Nrg1 and Ume6 play a role in a variety of regulatory and signaling pathways known to be important for C. albicans filamentous growth and virulence, 3) determine how specific host environmental cues control the transcriptional activity of Nrg1 and Ume6 both in vitro as well as in a mouse model of systemic candidiasis in vivo. A variety of genetic, molecular, biochemical and genomic approaches will be taken to achieve these aims. Because the ability of C. albicans to undergo a morphological conversion is required for virulence, these studies will also significantly improve our understanding of the underlying mechanisms of fungal pathogenesis and eventually lead to the development of more effective antifungal therapies