Abstract:

Spread by the bite of mosquitoes, malaria threatens over three billion people and causes 0.5 million deaths annually, thereby continuing to be a major global health problem. The absence of an effective vaccine and emerging drug resistant strains are grave concerns. Moreover, the parasite spreads by forming specialized cells that are unaffected by current antimalarial drugs. Notably, the host-vector transition presents a significant bottle-neck in the parasite’s life-cycle and could be the ‘achilles heel’ to target, for blocking the spread of malaria. We are interested in how dynamic ubiquitination regulates transmission of malaria parasites. Leveraging the rodent malaria model, P. berghei, to investigate early host-vector transition stages of the parasite, we identified ~1400 ubiquitin associated proteins, and >600 ubiquitylation sites in 240 unique proteins. A systematic genetic and phenotypic analysis of enzymes modulating ubiquitination identified several E3 ligases (Ub-writers) and deubiquitinases (Ub-erasers) that are essential to establish an infection in the host or/and the mosquito. We uncovered E3 ligases involved in maintaining the parasite’s cytoskeleton that impact shape and motility. We also discovered a parasite deubiquitinase which regulates the nuclear architecture of transmission competent cells and removal of the enzyme results in defective genome replication. Our results demonstrate ubiquitination is prevalent in the parasite during transmission and how divergent properties of parasite Ub-modulators could inform new transmission blocking strategies.

Bio:

Nisha did her PhD with Tim Haystead at Duke University, and her research examined the interaction of phosphorylation and ubiquitin pathways in the malaria parasite, P. falciparum. She then moved to Glasgow on a EMBO postdoctoral fellowship where she developed conditional genome engineering tools to study activity of enzymes that are essential at multiple stages of the parasite life-cycle.

In 2017, she started her research group at the Institute of Immunology and Infection research, University of Edinburgh. Her group is interested in what molecular mechanisms drive parasite-mosquito interactions and aspire to uncover new transmission-blocking strategies.

Note: This will be in in-person only seminar hosted by Yogesh Kulathu and Marcus Lee