Genomic Research Capacity Building for Cryptococcosis Translational Studies

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Abstract Cryptococcal meningitis (CM) is among the leading causes of death in 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 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 CM 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. Our University of Minnesota, Mbarara University of Science and Technology, and Makerere University research team has collaborated on CM clinical studies since 2009 – including three NIH-funded trials. While similar clinical infrastructures are now present throughout Africa, there is still limited ability to perform associated basic and translational research related to CM. Thus, we will continue to build the infrastructure, knowledge base, and human capacity among African investigators to perform basic research in genomics and immunology that is translatable to clinical practice. Our research group has made two key discoveries that influence patient mortality with CM: a) an immune signature associated with patient mortality, and b) that Cryptococcus genotype affects both patient mortality and immune response. Specifically, our preliminary genome-wide association studies (GWAS) identified 38 Cryptococcus genes associated with immune response and patient mortality in closely related Ugandan CM patient isolates. Thus, the scientific objective for this proposal is to define the impact of these Cryptococcus biomarkers on the immune response, and validate a subset of the biomarkers in a mouse model of cryptococcosis. Two specific aims will accomplish this goal. In the first aim, we will identify genomic differences and biomarkers in Cryptococcus isolates that influence patient mortality and neurocognitive deficits after CM that encompass the genetic diversity present in Uganda. 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 that can be used in clinical practice as the first step towards development of a diagnostic bioassay. Taken together, these translational studies will define the molecular processes underlying CM and translate this information (i.e. biomarkers) into novel clinical assays to identify high-risk individuals for acute mortality or neurological impairment who would benefit from tailored medical care.