Genomic Research Capacity Building for Cryptococcosis Translational Studies

ABSTRACT Cryptococcal meningitis (CM) is among the leading cause of death among all AIDS-related opportunistic infections and causes 15% of AIDS-related mortality globally. In Uganda, CM accounts for 60% of adult meningitis in hospitalized patients. Even with treatment, the current mortality rate for CM is 65%, with surviving patients often exhibiting significant neurological impairment. This poor survival is due to a complex interaction between 1) failure to control fungal replication and 2) deleterious host immune response. To reduce AIDS-related deaths, we must simultaneously mitigate Cryptococcus virulence while rebalancing detrimental host responses towards protective immunity. The long-term objective of our research team is to identify novel treatment strategies for CM that reduce morbidity and mortality associated with this devastating disease. The primary objective of this developmental research grant is to build the infrastructure, knowledge base, and human capacity among African investigators to perform basic research that is translatable to clinical practice. Our University of Minnesota and Mbarara University of Science and Technology research team has collaborated on CM clinical studies since 2005 ? including three NIH-funded trials ? yet there is still limited ability to perform associated basic research. This developmental grant will build human capacity in genomics, immunology, and animal models among African investigators by building upon our existing partnership to allow University of Minnesota investigators to mentor Mbarara University faculty and trainees through this project. Our research group has made two key discoveries that impact patient mortality with CM: a) an immune signature associated with patient mortality, and b) that Cryptococcus genotype affects both patient mortality and immune response. Thus, the scientific objective for this proposal is to understand the molecular processes underlying CM and translate this information (i.e. human and fungal biomarkers) into novel clinical practices to identify high- risk individuals for acute mortality or subsequent neurological impairment who would benefit from medical care tailored to promote a more effective immune response. Two specific aims will accomplish this goal. In the first aim, we will identify genomic differences in Cryptococcus strains that influence patient mortality and neurocognitive deficits after cryptococcal meningitis. We will then analyze associations between these genetic differences and patient immune responses in the second aim to define both fungal genetic and human immune biomarkers linked to mortality, fungal clearance, and altered mental status that can be used in clinical practice.