Understanding the role of malaria red blood cell binding proteins in invasion and host specificity

The zoonotic simian malaria parasite P. knowlesi, is a significant and emerging cause of morbidity and mortality in South-East Asia. P. vivax is closely-related, shares invasion pathways, and is the second biggest cause of malaria globally. Whilst P. vivax only infects humans, P. knowlesi can infect both humans and macaques, and this primate reservoir presents an extreme challenge for malaria control. Proteins that allow the parasite to invade red blood cells (RBCs) are known to be important determinants of virulence and host cell susceptibility, thus critical to understanding host-range.  Whilst it is known that binding of DBP to the DARC receptor on human RBCs is essential for invasion of both P. knowlesi (PkDBPa) and P. vivax (PvDBP), it is not known what this binding does, nor how various protein modifications including phosphorylation and proteolytic processing contribute to its function. Orthologue replacement approaches have been pioneered in P. knowlesi to study functions of orthologues from P. vivax– providing a platform to directly compare how PkDBPa and PvDBP affect invasion and underpin host range. Structural and biochemical studies will be used to examine how DBP orthologues interact with the DARC receptor (Higgins Lab, Oxford). This will also be informed by population genetics to understand the extent of polymorphisms in these key interacting domains (Campino Lab, LSHTM). Finally, the student will use fluorescent live-cell imaging of invasion to study these processes in real time, gaining new insights into how these proteins facilitate invasion and define host specificity.

Project details

Basic Science

Sep 2022 — Sep 2026

United Kingdom