Mechanistic insights into fungal pathogenicity and drug resistance using a novel lineage of Cryptococcus

Cryptococcus causes one of the most impactful fungal diseases in humans and is responsible for >220,000 cases and >130,000 deaths per year. Mortality is amplified by both innate and evolved drug resistance by this fungus and its ability for morphogenesis. I recently discovered a new genetically-distinct lineage of Cryptococcus through whole-genome sequencing of environmental isolates from Zambia, which has a reduced ability to cause disease in the murine model of infection and very high levels of antifungal resistance. In this project I will exploit this new lineage to gain mechanistic insight into fungal pathogenicity and drug resistance. I will perform comparative transcript profiling of all Cryptococcus lineages following infection of macrophages and antifungal drug exposure to identify genes responsible for those crucial phenotypic differences. Using the new lineage, I will construct a gene deletion library of unique gene differences and experimentally test them in relevant animal models to characterise novel drivers of pathogenicity. The genetic basis for pathogenicity and drug resistance will be complimented by delineating epigenetic determinants of those traits by constructing a comprehensive chromatin atlas across pathogenic morphotypes. This project will deliver new knowledge to address the important human health issues of cryptococcal infection and microbial drug resistance.