Plasmodium falciparum causes malaria disease during the asexual blood stages of infection when the merozoite invades erythrocytes and replicates. Merozoite surface proteins (MSPs) are proposed to play a role in the initial binding of merozoites to the erythrocyte, but precise roles remain undefined. Based on electron microscopy studies of invading Plasmodium merozoites, it is proposed that the majority of MSPs are cleaved and shed from the surface during invasion, perhaps to release receptor-ligand interactions. In this study, we demonstrate that there is not universal cleavage of MSPs during invasion. Instead, there is sequential and coordinated cleavage and shedding of proteins, indicating a diversity of roles for surface proteins during and after invasion. While MSP1 and peripheral surface proteins such as MSP3, MSP7, SERA4 and SERA5 are cleaved and shed at the tight junction between the invading merozoite and erythrocyte, the GPI-anchored proteins, MSP2 and MSP4, are carried into the erythrocyte without detectable processing. Following invasion, MSP2 rapidly degrades within ten minutes, whereas MSP4 is maintained for hours. This suggests that while some proteins that are shed on invasion may have roles in initial contact steps, others function during invasion and are then rapidly degraded, whereas others are internalized for roles during intra-erythrocytic development. Interestingly, anti-MSP2 antibodies did not inhibit invasion and instead were carried into the erythrocyte and maintained for approximately 20 hours without inhibiting parasite development. These findings provide new insights into the mechanisms of invasion and knowledge to advance the development of new drugs and vaccines against malaria.
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Funding was provided by the National Health and Medical Research Council of Australia (program grant to J.G.B.; Infrastructure for Research Institutes Support Scheme grant), the Australian Research Council (future fellowship to J.G.B.), and a Victorian State Government operational infrastructure support grant. A postgraduate research fellowship to M.J.B. was provided by the Australian Government and the University of Melbourne Department of Medicine, Dentistry and Health Sciences.