Crypto-Division: Discovering non-canonical mechanisms of genome transmission in the human fungal pathogen Cryptococcus neoformans

Invasive fungal diseases threaten human health. The paucity of treatments, combined with resistance to anti-fungal drugs means there is an urgent need for new treatments. Cryptococcus neoformans is an understudied human fungal pathogen, causing ~200,000 annual cases worldwide of Cryptococcal meningitis. C.neoformans heads the World Health Organisation critical-priority list of fungal pathogens, which pose the greatest threat to public health and have the largest knowledge deficits. This pathogen exhibits aneuploidy-mediated anti-fungal drug resistance. We will dedicate the wide-ranging expertise of our team to pursue mechanistic conservation and divergence between C.neoformans cell divisions and human mitosis. We will identify fungal-specific mechanisms of kinetochore-microtubule attachment by reconstituting its entire kinetochore. During infection, C.neoformans forms self-protective, polyploid titan cells. We will investigate ploidy-specific variations of chromosome segregation in titan cells and their production of haploid and aneuploid daughter cells. Mitotic progression and accurate chromosome segregation are ensured by carefully balanced activities of kinases and phosphatases. We will dissect these controls in Cryptococcal divisions and study the consequences of genetic and drug-induced perturbation. Thus, we aim to discover novel C. neoformans-specific chromosome segregation mechanisms and cell cycle vulnerabilities of a critical-priority human fungal pathogen with the ultimate goal of identifying potential therapeutic targets.