An abundant merozoite surface protein of Plasmodium falciparum modulates susceptibility to inhibitory antibodies

Abstract Malaria merozoite surface proteins (MSPs), are thought to have important roles in red blood cell (RBC) invasion and their exposure on the parasite surface makes them attractive vaccine candidates. However, their role in invasion has not been directly demonstrated and their biological functions are unknown. One of the most abundant proteins is Pf MSP2, which is likely an ancestral protein that has been maintained in the Plasmodium falciparum lineage and is a focus of vaccine development, whose function remains unknown. Using CRISPR-Cas9 gene-editing, we removed Pf MSP2 from two different P. falciparum lines with no impact on parasite replication or phenotype in vitro , demonstrating that it is not essential for RBC invasion. However, loss of Pf MSP2 led to increased inhibitory potency of antibodies targeting other merozoite proteins involved in invasion, particularly Pf AMA1. In a solid-phase model, increasing concentrations of Pf MSP2 protein reduced binding of different antibodies against Pf AMA1 in a dose dependent manner. These data suggest that Pf MSP2 can modulate the susceptibility of merozoites to protective inhibitory antibodies. The results of this study change our understanding of the potential functions of Pf MSP2 and establishes a new concept in malaria where a surface protein can reduce the protective efficacy of antibodies targeting a different antigen. These findings have important implications for understanding malaria immunity and informing vaccine development.