Roles of Cryptococcus cell wall dynamics during infection and antifungal drug resistance

This project aims to understand how antifungal drugs affect the Cryptococcus neoformans cell wall composition during infection.

Fungal meningitis caused by Cryptococcus neoformans is associated with extremely high mortality ranging from 40% to 70% all patients in high income and low income countries, respectively. New interventions are required to mitigate this unmet clinical need. In order to generate new drugs, we need to better understand the mechanisms used by C. neoformans to cause disease.

The cell wall has been extensively studies in other fungal pathogens and is a target of antifungal drugs such Echinocandins. Yet, there is very little published information on the C. neoformans cell wall during infection.

Using biochemical and structural analyses, I will determine the cell wall composition of C. neoformans strains grown under host mimicking conditions in the presence and absence of antifungal drugs.

The strains will be exposed to individual drugs and to drug combinations mimicking clinically used anti-Cryptococcus therapies.

Importantly, I will correlate my findings with analyses of cell wall of isolates taken directly from patients in Uganda before antifungal treatment and after 7 days of therapy to determine how antifungals affect the cell wall in vivo.

In addition, I will examine how antifungal drugs in clinical use influence the expression of cell wall biosynthesis genes in drug sensitive and drug-resistant clinical isolates.

These studies will reveal critical new insights into C. neoformans cell wall dynamics during antifungal therapy, and will likely identify cell wall components to target for future antifungal drug development.