An abundant merozoite surface protein of <i>Plasmodium falciparum</i> 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 remain unknown. One of the most abundant merozoite surface proteins is <i>Pf</i>MSP2, a likely ancestral protein that has been maintained in the <i>Plasmodium falciparum</i> lineage and is a focus of vaccine development. Using CRISPR-Cas9 gene editing, we removed <i>Pf</i>MSP2 from two different <i>P. falciparum</i> lines with no impact on parasite replication or phenotype in vitro, demonstrating that it is not essential for RBC invasion. Interestingly, loss of <i>Pf</i>MSP2 led to increased inhibitory potency of antibodies targeting other merozoite proteins involved in invasion, particularly <i>Pf</i>AMA1. In a solid-phase model, increasing concentrations of <i>Pf</i>MSP2 protein reduced binding of different antibodies against <i>Pf</i>AMA1 in a dose-dependent manner. These data suggest that <i>Pf</i>MSP2 can modulate the susceptibility of merozoites to protective inhibitory antibodies. The results of this study change our understanding of the potential functions of <i>Pf</i>MSP2 and establish 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.