Candida albicans is an opportunistic pathogen of AIDS patients. These individuals typically develop oral and esophageal infections due to this fungus. More recently, candidemia has been recognized as a nosocomial complication in AIDS patients with significant associated mortality. Long-term and prophylactic antifungal treatment of AIDS patients has resulted in the emergence of clinically resistant C. albicans strains. This situation is exacerbated by the limited arsenal of efficacious drugs. Much of the biology of C. albicans is unknown due, in part, to the past difficulties in the genetic manipulation of this fungus. However, a substantial amount of data implicate the dimorphic ability of C. albicans in the development of disease. In the case of C. albicans, dimorphism refers to the ability of this organism to adopt either a yeast (single-celled) or hyphal (multicellular filamentous) morphology. The relatively recent development of methods to overcome many of the technical problems in the genetic dissection of C. albicans now permits a closer mechanistic examination of the role of dimorphism in disease.
The aim of the present proposal is the investigation of a particular genetic determinant of dimorphism in C. albicans, the gene HWP1. HWP1 was isolated in a screen for genes expressed only in the filamentous form. HWP1 is required for filamentation and virulence in a mouse model of systemic disease, but is not required for gastrointestinal infection in mice nor for filament formation in the gut. This is the first demonstration that the pathogenic attribute of dimorphism has biological facets unique to mucosal vs. systemic disease. The investigators propose a series of molecular genetic studies to define the mechanism(s) governing the development-specific expression of HWP1 in vitro and in vivo and the function of the encoded protein in hyphal development. These studies are set forth with the long-term objective of understanding the molecular basis of pathogenesis by C. albicans and that this knowledge may contribute to better approaches to disease prevention and treatment.
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