Abstract

Malaria parasites rely on cycles of cellular invasion and intracellular growth to proliferate within the blood stream, a process which underpins symptoms of the disease. The cycles of cellular invasion and intracellular growthThe adaptation of P. knowlesi (Pk) to culture in human erythrocytes presents exciting opportunities to study erythrocyte invasion biology. Two major protein families have been studied extensively in P. falciparum (Pf): the erythrocyte binding-like proteins (EBPs/EBAs) and the reticulocyte binding-like proteins (RBLs/RHs). These proteins are hypothesized to have overlapping but critical roles during the invasion process. The zoonotic malaria parasite P. knowlesi, has a smaller repertoire of these proteins, and much larger and polarised invasive stages known as merozoites.

Employing a conditional knockout approach, we’ve demonstrated distinct roles for the two families at different invasion stages, including a specific role for RBL proteins in the initial identification and deformation of target host erythrocytes. Furthermore, we’ve unearthed new features that prompt a significant reassessment of invasion. Notably, we’ve discovered that Pk merozoites can engage in productive gliding motility prior to invasion, and we’ve corrected a longstanding assumption in merozoite topology – the merozoite apex is actually located in the wider end of the cell, contrary to prior beliefs. These findings unveil new aspects of this complex process and introduce fresh tools and techniques to deepen our understanding of invasion across all malaria parasite species. Finally, we will demonstrate how the new genetic tools emerging from studies in basic biology of malaria parasite can be readily adapted to facilitate vaccine, drug and diagnostics targeting a broader range of malaria parasite species.