Candida albicans is one of the most frequently isolated fungal pathogens of humans. It is a permanent resident of the healthy gastrointestinal microbiome, existing mostly as the yeast form. But when host immunity is impaired, disseminated C. albicans infections can occur with a high mortality rate. A critical virulence attribute of C. albicans is its morphogenetic plasticity. In response to host environmental cues, this fungus can grow as yeast, pseudohyphal, and hyphal forms. Mutants that are defective in hyphal formation display attenuated virulence in animal models of systemic candidiasis. Our long-term goal is to understand the signaling pathways that govern C. albicans morphogenesis. Recent studies from our laboratory show that hyphal development consists of two temporally linked phases, initiation and maintenance. Initiation requires the Ras-cAMP-protein kinase A (PKA) pathway that regulates the rapid but temporary disappearance of the Nrg1 transcriptional repressor of hyphal development. Maintenance requires the Brg1 transcription factor-mediated promoter chromatin remodeling of hypha-specific genes in response to nutrient limitation in air or stabilization of the Ume6 transcriptional activator under hypoxia and hypercapnia. Aim 1 will characterize the C. albicans hyphal initiation pathways that are essential for systemic infection. We will study how C. albicans cells integrate signals from N- acetylglucosamine, amino acids and pH to control hyphal initiation programs. Aim 2 will use mutant screens and genetic analysis to uncover signaling pathways that sense hypoxia, high CO2, and iron depletion to sustain hyphal elongation in systemic infection. This proposal will gain molecular insights into how host signals are sensed by C. albicans to control hyphal development during infection, which is critically important in understanding its pathogenicity. The results of these in-depth investigations will provide new insight into the mechanisms that govern hyphal initiation and maintenance in an important fungal pathogen, and will serve as the foundation for novel therapeutic strategies against C. albicans. Furthermore, the signaling pathways to be examined in this application are likely conserved among diverse fungal pathogens. Data from these studies will provide insight into signaling pathways that govern virulence in other fungi.