Matt Higgins wins Wellcome Trust New Investigator Award for malarial studies
University Lecturer Matt Higgins has been awarded a prestigious New Investigator Award from the Wellcome Trust. The generously funded 7 year long award will support his work, in which he sheds light on the molecular interactions at the heart of malaria pathology.
Structure of the DBL3X domain from the var2csa protein essential in pregnancy-associated malaria
(Click to enlarge)
Malaria is the most deadly parasitic disease of humans, causing a major health burden worldwide, with around one million deaths a year and hundreds of millions of serious cases. The complex life-cycle of the single celled Plasmodium parasite which causes the disease and its ability to evade the immune system have thwarted vaccine development.
Dr Higgins will target specific malarial surface proteins that are key vaccine candidates and will investigate how they interact with their human ligands.
‘In the past, vaccine development for malaria was hampered by reliancy on relative few characterised antigens on which vaccines were based,’ explains Dr Higgins. ‘But parasite genome sequences have allowed knowledge of parasite biology to leap forward so the key points at which it is susceptible are now becoming more and more apparent.’
The malaria parasite, Plasmodium falciparum, destroying red blood cells in the liver (photograph by Albert Bonniers Forlag, National Geographic) (Click to enlarge)
Detailed molecular characterisation of proteins identified as key vaccine candidates is lacking though, and this is where Dr Higgins hopes his research will have an impact. He will focus on proteins containing the Rh and DBL structural motifs that are unique to the malarial parasite. Two of these proteins, Rh5 and DBP, play crucial roles in its ability to invade red blood cells, an essential part of the parasite life cycle. A third, VAR2CSA, is essential in pregnancy-associated malaria.
Although these proteins can diversify and evade immune detection, they are under selective pressure to maintain conserved sites that mediate their function. This provides an opportunity for targeted vaccine design, explains Dr Higgins. ‘We need to understand how these proteins bind to their ligands, and to inhibitory antibodies, so that we can help vaccine developers to focus immunity onto those conserved and functionally important regions’ he says.
The group is already set up to produce large quantities of malarial surface proteins and their ligands. Using a range of state-of-the-art-tools, it will thoroughly characterise the proteins’ molecular structures and explore how they interact with their ligands.
Structure of a malarial parasite PfEMP1 protein (related to var2csa) bound to the endothelial ligand ICAM1, determined by small angle X-ray scattering (Click to enlarge)
One of the proteins the group will study is already showing promise. Rh5, which was only recently discovered to be essential to the parasite, interacts with the erythrocyte protein basigin. It shows little polymorphism, and antibodies against protein from one strain inhibit parasite invasion of the most divergent strains. Whilst a long-term solution to malarial prevention focuses on designing a vaccine against this antigen, antibodies against it could be used to give short-term protection to visitors to malarial regions.
Dr Higgins’ detailed characterisation of the proteins will be partnered by clinical malarial expertise locally and internationally including with colleagues at the Jenner Institute in Oxford and the Centre for Medical Parasitology in Copenhagen. His work will help them to select and design vaccine components.
The proximity of the Jenner Institute, a world-leader in malaria vaccine development whose expertise spans in vitro parasite culture work through to clinical trials, has proved beneficial to Dr Higgins. ‘Oxford is one of the very best places for doing malarial epidemiology and vaccinology,’ he comments.
The New Investigator Award will be complemented by other structural work in Dr Higgins’ lab looking at receptor proteins from the cell surface of the trypanosome parasite in collaboration with Professor Mark Carrington from the University of Cambridge.