• The N-terminal subunit of MSP1 binds to a specific polypeptide region of GPA during merozoite invasion of human RBCs.• The GPA-band 3 complex plays an essential role during malaria parasite invasion.Plasmodium falciparum invasion of human red blood cells (RBCs) is an intricate process requiring a number of distinct ligand-receptor interactions at the merozoite-erythrocyte interface. Merozoite surface protein 1 (MSP1), a highly abundant ligand coating the merozoite surface in all species of malaria parasites, is essential for RBC invasion and considered a leading candidate for inclusion in a multiple-subunit vaccine against malaria. Our previous studies identified an interaction between the carboxyl-terminus of MSP1 and RBC band 3. Here, by employing phage display technology, we report a novel interaction between the amino-terminus of MSP1 and RBC glycophorin A (GPA). Mapping of the binding domains established a direct interaction between malaria MSP1 and human GPA within a region of MSP1 known to potently inhibit P falciparum invasion of human RBCs. Furthermore, a genetically modified mouse model lacking the GPA-band 3 complex in RBCs is completely resistant to malaria infection in vivo. These findings suggest an essential role of the MSP1-GPA-band 3 complex during the initial adhesion phase of malaria parasite invasion of RBCs. (Blood. 2015;125(17):2704-2711
IntroductionMalaria remains one of the most common and deadly parasitic diseases in the world. The World Health Organization estimates that 5% to 9% of the global population is infected by malaria annually, resulting in over 700 000 deaths.1 Children younger than 5 years are most vulnerable to Plasmodium falciparum, the most lethal species among 4 malaria parasites that commonly infect humans. Malaria also takes an enormous economic toll by impacting the economies of most endemic countries, particularly in sub-Saharan Africa. Historically, vaccines have been one of the most effective means of controlling infectious diseases. Accumulating evidence suggests that a malaria vaccine can be developed 2,3 ; however, most malaria vaccine candidate antigens have suffered limitations of low immunogenicity and efficacy. To date, no licensed vaccine exists for malaria despite the urgent global need.Clinical manifestation and mortality in malaria is directly associated with the blood stage of the parasite life cycle. The invasion process consists of multiple molecular events during which red blood cell (RBC) membrane proteins and merozoite-coat proteins are engaged in specific receptor-ligand interactions to form unique invasion pathways. 4,5 Continued interest in developing a multiantigen malaria vaccine has drawn much attention to parasite proteins localized on the surface and at the apical end of the merozoite as potential vaccine candidates. 4 Merozoite surface protein 1 (MSP1) is a major ligand coating the surface of merozoites in all species of malaria parasites 6 and is considered one of the leading candidates for inclusion in a multiplesubunit vaccine against...