Tissue specific immunity to fungal infections

Project summary/abstract Candida albicans is a major opportunistic fungal pathogen of humans, which colonizes mucosal surfaces (oral, gut, vaginal tract) in many individuals and can cause serious systemic (i.e., invasive candidiasis) and mucosal infections (e.g. oropharyngeal candidiasis) in immunocompromised patients. Although it is well established that the oral mucosal and systemic infection niches impose differential immune pressures on C. albicans, the mechanisms by which C. albicans adapts to such distinct environments are still very poorly understood. This proposal is built on the hypothesis, supported by our extensive preliminary data, that C. albicans adaptation and virulence in these distinct host niches require the Gcn5 lysine acetyl transferase, which acetylates different sets of cellular proteins during invasive vs. oral infection, thus regulating their activities during the host-pathogen interaction. Gcn5 is known to play a key role chromatin remodeling and the regulation of gene expression. Our preliminary studies have revealed that Gcn5 is essential for antifungal drug resistance and for virulence in both the oropharyngeal as well as the invasive candidiasis mouse models. We have identified Eaf3, a Gcn5 acetylation substrate that may be important for C. albicans virulence in an organ specific manner. Thus, despite clear evidence for acetylation-mediated contributions to fungal pathogenesis, there is a knowledge gap in our understanding of how fungal the acetylome change in vivo during infection and organ dissemination. Thus, there is a critical need to analyze fungal pathogens recovered directly from host niches in vivo, where they encounter complex and dynamic immune defense. The overall objective in this application is to decipher how Gcn5 mediated acetylation are modified in vivo in response to host immune defenses in a niche-specific manner. These objectives are strongly supported by preliminary data, which shows that Gcn5 target Eaf3 is specific for virulence in invasive candidiasis and the acetylation of Eaf3 is required for niche specific virulence of C. albicans. Based on the preliminary data, our central hypothesis is that Gcn5 regulated acetylome confer distinct adaptive capacities to C. albicans, depending on niche-specific host defenses. We will test our central hypothesis and accomplish our objective by pursuing two Specific Aims. 1) Identify the in vivo targets of C. albicans Gcn5 in a murine model of oropharyngeal candidiasis and characterize their roles in the fungal interaction with mucosal immunity. 2) Identify the in vivo targets of C. albicans Gcn5 in a murine model of invasive candidiasis and characterize their roles in the fungal interaction with systemic immune system. The payoffs of this proposal are expected to be significant because we expect to uncover organ/tissue specific determinants of C. albicans virulence.