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. 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 know
binding 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, nor
how various protein modifications including phosphorylation and proteolytic processing
contribute to its function. We have pioneered orthologue replacement approaches 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. The
project will dissect the functional role of domains, posttranslational modifications,
ligand-receptor interactions comparatively across both Pv and PkDBP using cuttingedge
Bar-Seq approaches to study pooled parasite expressing DBP variants (Moon Lab,
LSHTM). 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.