Grant: Project Grant

Cryptococcus neoformans is a globally distributed soil fungus that is responsible for 147,000 deaths annually. C. neoformans infection begins in the lungs and frequently moves to the brain where it causes life-threatening meningitis. In addition to being particularly dangerous for those with weakened immune defences there is an increasing recognition that this pathogen may infect healthy humans. Interestingly, only a fraction of all individuals that are exposed to C. neoformans will become ill. We believe that humans have natural genetic differences that influence their susceptibility to severe cryptococcal infection and their response to treatment; however, we lack a firm understanding of the basic mechanisms that control these differences. Precise knowledge of how host immunity controls C. neoformans infection would be extremely valuable for screening, risk prediction, and disease management. Using a mouse model that closely resembles human infection we have identified two genes that participate in the development of severe cryptococcal disease. We will apply cutting edge technology to determine if these two genes work cooperatively and will identify the underlying pathways that control immunity in cells, tissues, and organs. Finally, we will determine whether interfering with the function of these two genes will improve host resistance to C. neoformans infection. The knowledge we derive through this project will be valuable for developing novel therapies that boost the inflammatory and immune responses of affected individuals and reduce the disability and death caused by serious human fungal infection.