Grant: Operating Grant - Priority Announcement: Infection and Immunity (Bridge Funding)

Infectious diseases are a major threat to human health and account for 25% of all deaths throughout the world. Fungal infections are particularly dangerous for individuals with weakened immune defenses due to conditions such as advanced or severe chronic illness, HIV infection, cancer treatment, or organ transplantation. During the past three decades, Cryptococcus neoformans has emerged as a serious global human fungal pathogen that may cause fatal infection involving the lungs and brain. The basic mechanisms by which humans defend themselves against this fungus are not well understood. Using a mouse model that closely resembles the human disease we have identified three important chromosomal regions, or loci, that control the development of severe cryptococcal infection. The first aim of this proposal is to complete the identification of the loci that control antifungal immunity in our model. Second, we will use genetic tools to dissect apart the effects of each locus on host immunity. Third, we will analyze the effects of each individual locus on the immune response of lung cells and tissue against Cryptococcus neoformans. Finally, we will focus on the precise identity of the host resistance genes contained within each locus by combining the information we have gathered with a series of modern molecular technologies. The knowledge arising from this research will advance our understanding of how serious fungal diseases develop and will have excellent potential to improve prevention and treatment measures for individuals as well as for the population.