Molecular dissection of the host-parasite interactions underlying malaria parasite erythrocyte invasion (360G-Wellcome-225844_Z_22_Z)

Symptoms of malaria are associated with cycles of host erythrocyte invasion. Merozoites, the specialised invasive parasite stages, contain a range of specific structures, secretory organelles and a molecular motor to target host receptors and invade. Proteins involved in this process are key determinants of virulence and potential vaccine candidates. The zoonotic malaria parasite Plasmodium knowlesi (Pk) is ideal for studying invasion, and our work to establish its in-vitro propagation, real-time imaging and CRISPR-Cas9 genome- editing has created an unparalleled system for malaria experimental genetics. Invasion of red blood cells is not one process but many. Each discrete step requires distinct parasite ligand/host receptor interactions and resolving conditions, to allow progression to the next. In this project we aim to unravel the temporal mechanics of merozoite invasion through building an integrative and comparative understanding of four key processes: merozoite gliding, deformation, invasion commitment and reorientation. We will meld our pioneering Pk genetic pipeline with spatial-proteomics, detailed phenotypic screens and comprehensive functional analyses of key proteins and their molecular and biophysical role within each step. Finally, we will apply comparative biology to test key paralogs in human-infecting P. falciparum and Pk, to develop critical genus-wide understanding of invasion.