Abstract
Plasmodium falciparum, the parasite responsible for severe malaria, develops within erythrocytes. Merozoite invasion and subsequent egress of intraerythrocytic parasites are essential for this erythrocytic cycle, parasite survival and pathogenesis. In the present study, we report the essential role of a novel protein, P. falciparum Merozoite Surface Antigen 180 (PfMSA180), which is conserved across Plasmodium species and recently shown to be associated with the P. vivax merozoite surface. Here, we studied MSA180 expression, processing, localization and function in P. falciparum blood stages. Initially we examined its role in invasion, a process mediated by multiple ligand-receptor interactions and an attractive step for targeting with inhibitory antibodies through the development of a malaria vaccine. Using antibodies specific for different regions of PfMSA180, together with a parasite containing a conditional pfmsa180-gene knockout generated using CRISPR/Cas9 and DiCre recombinase technology, we demonstrate that this protein is unlikely to play a crucial role in erythrocyte invasion. However, deletion of the pfmsa180 gene resulted in a severe egress defect, preventing schizont rupture and blocking the erythrocytic cycle. Our study highlights an essential role of PfMSA180 in parasite egress, which could be targeted through the development of a novel malaria intervention strategy.
Highlights
Plasmodium falciparum, the parasite responsible for severe malaria, develops within erythrocytes
Both Merozoite Surface Antigen 180 (MSA180) and SERA6 are substrates of a subtilisin-like protease called SUB116, which is secreted from exonemes into the parasitophorous vacuole (PV) at the start of the proteolytic cascade culminating in the sequential rupture of the PV membrane (PVM) and the erythrocyte plasma membrane
We first identified and selected PfMSA180 based on the similarity of its gene expression profile to that of well-characterised merozoite invasion ligands of the Erythrocyte Binding Antigen (EBA) and Rhoptry protein Homolog (RH) families, during late schizogony
Summary
Plasmodium falciparum, the parasite responsible for severe malaria, develops within erythrocytes. Another study by Tan et al.[16] published earlier this year whilst this manuscript was under review identified MSA180 as a critical co-factor for SERA6, a parasitophorous vacuole (PV)-localized cysteine protease involved in dismantling of the erythrocyte cytoskeleton during merozoite egress. Both MSA180 and SERA6 are substrates of a subtilisin-like protease called SUB116, which is secreted from exonemes into the PV at the start of the proteolytic cascade culminating in the sequential rupture of the PV membrane (PVM) and the erythrocyte plasma membrane. MSA180 is conserved across the Plasmodium genus and may serve as an essential protein involved in egress in all species, lending itself as a promising target for the design of parasite egress inhibitors and new therapeutic interventions
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