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

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The zoonotic simian malaria parasite P. knowlesi, is a significant and emerging causeof morbidity and mortality in South-East Asia. P. vivax is closely-related, sharesinvasion pathways, and is the second biggest cause of malaria globally. Whilst P. vivaxonly infects humans, P. knowlesi can infect both humans and macaques, and thisprimate reservoir presents an extreme challenge for malaria control. Proteins thatallow the parasite to invade red blood cells (RBCs) are known to be importantdeterminants of virulence and host cell susceptibility, thus critical to understandinghost-range. The project aims to understand the role of the Duffy binding protein (DBP),a malaria parasite protein which is required to bind and invade RBCs. Whilst we knowbinding of DBP to the DARC receptor on human RBCs is essential for invasion of both P.knowlesi (PkDBPa) and P. vivax (PvDBP), we do not know what this binding does, norhow various protein modifications including phosphorylation and proteolytic processingcontribute to its function. We have pioneered orthologue replacement approaches in P.knowlesi to study functions of orthologues from P. vivax- providing a platform todirectly compare how PkDBPa and PvDBP affect invasion and underpin host range. Theproject will dissect the functional role of domains, posttranslational modifications,ligand-receptor interactions comparatively across both Pv and PkDBP using cuttingedgeBar-Seq approaches to study pooled parasite expressing DBP variants (Moon Lab,LSHTM). Structural and biochemical studies will be used to examine how DBPorthologues interact with the DARC receptor (Higgins Lab, Oxford). This will also beinformed by population genetics to understand the extent of polymorphisms in thesekey interacting domains (Campino Lab, LSHTM). Finally, the student will usefluorescent live-cell imaging of invasion to study these processes in real time, gainingnew insights into how these proteins facilitate invasion and define host specificity.