‘It’s a match!’: Uncovering the functions of sexual-stage malaria parasite vaccine targets
Transmission Blocking Vaccines (TBVs) decrease man-to-mosquito malaria parasite transmission by interfering with the intra-mosquito parasite development. After decades of preclinical development, two TBV antigens are being tested in clinical trials at Radboudumc and elsewhere (e.g. NCT04862416). Both vaccines are based on proteins, Pfs230 and Pfs48/45, that are part of an essential complex on the surface of sexual-stage parasites, gametocytes. Despite these fantastic developments, very little is known about the exact, possibly sex-specific, functions of these proteins in parasite fertilization. Recently, our department helped developing a genetically engineered gametocyte producer line [PMID:34376675], opening up new avenues for the molecular characterization of gametocytes to aid the development of next-generation vaccines.
In this project, we will study the (sex-specific) role(s) of Pfs230 and Pfs48/45 using two complementary approaches. First, we will investigate these proteins’ in vivo function and whether it differs between male and female gametocytes by developing and characterizing sex-specific loss-of-function mutants, building on our department’s expertise in creating transgenic parasites [PMID:34376675], and/or using sex-specific antimalarials [PMID:29422384]. Moreover, gametocyte mating will be visualized by live imaging of fluorescently labelled (knockout) parasites. Finally, we will use clinical isolates to investigate whether geographically fixed mutations known in the otherwise well conserved proteins might impair their mating compatibility.
In our second research line, we will investigate the molecular function of the Pfs230-Pfs48/45 complex in greater detail. In collaboration with Jean-Philipe Julien (University of Toronto), we will determine the structure of an affinity-purified complex using cryo-EM. In addition, we will use complexome profiling, a technique recently used for the first time on malaria by our department [PMID:34155201], to shed light on their interaction partners. This project will yield unprecedented insights in the molecular mechanisms of a poorly-understood but clinically relevant part of the P. falciparum life cycle, thus contributing to the development of future TBVs.