Candida albicans, the major human fungal pathogen, is the leading cause of oral candidiasis worldwide and fourth leading cause of hospital-acquired bloodstream infections in the U.S. Approximately 25% of AIDS patients acquire oral candidiasis. Immunocompromised individuals, such as cancer patients on chemotherapy and organ transplant recipients, are also highly susceptible to infection. Oral infections have become more difficult to treat due to a limited number of antifungal drugs and increased frequency of drug-resistant isolates. C. albicans virulence requires the ability to undergo a reversible transition from yeast (single ovoid, budding cells) to pseudohyphal and hyphal filaments (elongated cells attached end-to-end) in response to host environmental conditions such as serum, body temperature (37?C) and neutral pH. This transition allows for efficient C. albicans tissue invasion (including invasion of the oral mucosa), immune evasion, dissemination and is associated with the expression of genes important for filamentation, as well as a wide variety of additional virulence-related processes. While many filament-specific target genes have been identified, considerably less is known about C. albicans filamentous growth signaling pathways and regulatory circuits. Therefore, our long-term goal is to gain a better understanding of the molecular mechanisms that control regulatory circuits important for C. albicans morphology and virulence. Towards this goal, we have recently demonstrated that a C. albicans serine/threonine protein phosphatase type 2A (PP2A), Ppg1, is important for morphogenesis in both solid and liquid medium and controls down-regulation of a key transcriptional repressor of filament-specific target genes in response to strong filament-inducing conditions. Our hypothesis is that the Ppg1 phosphatase plays a key role in controlling C. albicans morphology, virulence and virulence-related processes. This hypothesis will be addressed by the following specific aims: 1) determine the genetic and functional relationship between PPG1 and other components of C. albicans filamentous growth signaling and regulatory circuits, 2) determine the requirement of Ppg1 phosphatase activity for C. albicans morphogenesis, virulence and virulence-related processes. These studies are significant because gaining a better understanding of regulatory circuits that control C. albicans filamentous growth and virulence will provide information that may eventually lead to the development of novel and more effective antifungal strategies to treat oral and systemic candidiasis.
Worldwide, Candida albicans is the most common cause of oral fungal infections. This project will significantly improve our understanding of the mechanisms that control C. albicans morphology and virulence. These studies are also likely to provide information leading to the identification of potential targets for the development of novel and more effective antifungal therapies.