Candida albicans represents one of the most prevalent opportunistic pathogens that cause disease in HIV+ patients. In fact, prior to the introduction of HAART therapies, C. albicans infections were considered predictive for AIDS diagnoses. C. albicans is a fungal pathogen that can infect virtually any tissue within the host and in HIV+ patients, it causes severe oral-pharyngeal candidiasis (OPC). The ability to respond to extracellular pH is essential for C. albicans pathogenesis and the oral-pharyngeal tract, which is generally a neutral-alkaline environment, can show marked pH variation depending on a number of factors. We have identified a signal transduction pathway, which culminates with activation of the Rim101p transcription factor by proteolytic processing. Rim101p governs expression of genes required for optimal growth at neutral-alkaline pH and is required for OPC. Thus, the long-term objective of our research is to determine how the RIM101 pathway senses environmental pH and responds to promote OPC. We will determine how the upstream members of the RIM101 pathway promote pH-dependent Rim101p processing and how processing contributes to Rim101p activity. We will determine how Rim101p promotes changes in gene expression and how the targets of the RIM101 pathway contribute to the neutral-alkaline pH responses and promote pathogenesis. We will also determine how the RIM101 pathway contributes to the interaction with host epithelial cells and OPC. From these studies, we will establish a framework to understand how Rim101p contributes to the success of C. albicans as an opportunistic pathogen. Further, because the RIM101 pathway promotes OPC, the information generated from these studies may provide insights into new treatment regimens and will identify new targets, including those factors that promote Rim101p processing, for potential drug development in order to prevent or treat OPC in the HIV+ population.
