Candida albicans is a commensal fungus residing in the oral, gastrointestinal cavities, and the vagina of humans and other warm-blooded animals. It is also an opportunistic pathogen with a disease spectrum ranging from mild superficial infections in overall healthy people to wide-spread, deep-seated and life-threatening infections in patients who's immune system is severely compromised by underlying disease. C. albicans is the 4th most common microorganism causing nosocomial blood stream infections representing a serious public health challenge of increasing medical and socio-economical importance In previous work, we detected higher rates of phenotypic and chromosome-level genetic variation following passage of C. albicans in vivo than after propagation for a similar number of generations in vitro. In contrast, the rate of short-range recombination (LOH) events per cell division was similar following passage in vivo and in vitro. We concluded that conditions during infectious growth affect chromosome disjunction more strongly than they affect mitotic cross-over or other recombination processes and that the differing spectrum of short- and long-range LOH events must reflect the different selective environment represented by in vitro vs in vivo propagation. We are just beginning to understand by which mechanisms C. albicans adapts to different host environments, whether these changes are triggered by the host, and how the fungus modulates antigenic properties through variations of surface proteins. Our working hypothesis is that the adaptation of C. albicans through genetic changes during infection may play a bigger than anticipated role in host-pathogen interactions. Our goal is to study what is necessary to maintain the host-pathogen balance from the perspective of the fungus. In particular, how do the high levels of genetic and phenotypic variation that we find in strains exposed to the host affect the fitness of the fungus and how do such alterations in fitness influence the host-pathogen interaction. We will study two large post-in vivo sets of isolates from an oropharyngeal candidiasis (OPC) model and a blood stream infection (BSI) model to address several important questions in this proposal: 1) Do host niches such as the oral cavity and bloodstream cause similar types of increased genetic and phenotypic diversity? 2) Does exposure to host niches induce novel genotypes? 3) Does growth in the host select for altered fitness and or virulence? and 4) Do cell wall associated genes contribute to antigenic variation? Our studies will advance our understanding of host-pathogen interactions from the pathogen's perspective and will aid us in revealing how the host and the fungus maintain their balanced relationship in healthy individuals as well as how disruption of this interaction causes devastating infections in the immuno-compromised host. PUBLIC HEALTH RELEVANCE: Fungal infections are a serious health concern for immuno-compromised patients, such as those with HIV/AIDS, cancer patients or patients receiving organ transplants. Fungal infections occur at many body locations and can infect virtually all organs in the human body. The proposed work will address basic questions on host-fungus interactions with the goal of advancing our understanding of how the host and the fungus maintain their balanced relationship in healthy individuals as well as how disruption of this interaction causes devastating infections in the immuno-compromised host.