RH5–Basigin interaction plays a major role in the host tropism of Plasmodium falciparum

Abstract

Plasmodium falciparum, the cause of almost all human malaria mortality, is a member of the Laverania subgenus which infects African great apes. Interestingly, Laverania parasites exhibit strict host specificity in their natural environment: P. reichenowi, P. billcollinsi, and P. gaboni infect only chimpanzees; P. praefalciparum, P. blacklocki, and P. adleri are restricted to gorillas, and P. falciparum is pandemic in humans. The molecular mechanism(s) responsible for these host restrictions are not understood, although the interaction between the parasite blood-stage invasion ligand EBA175 and the host erythrocyte receptor Glycophorin-A (GYPA) has been implicated previously. We reexamined the role of the EBA175-GYPA interaction in host tropism using recombinant proteins and biophysical assays and found that EBA175 orthologs from the chimpanzee-restricted parasites P. reichenowi and P. billcollinsi both bound to human GYPA with affinities similar to that of P. falciparum, suggesting that the EBA175-GYPA interaction is unlikely to be the sole determinant of Laverania host specificity. We next investigated the contribution of the recently discovered Reticulocyte-binding protein Homolog 5 (RH5)-Basigin (BSG) interaction in host-species selectivity and found that P. falciparum RH5 bound chimpanzee BSG with a significantly lower affinity than human BSG and did not bind gorilla BSG, mirroring the known host tropism of P. falciparum. Using site-directed mutagenesis, we identified residues in BSG that are responsible for the species specificity of PfRH5 binding. Consistent with the essential role of the PfRH5-BSG interaction in erythrocyte invasion, we conclude that species-specific differences in the BSG receptor provide a molecular explanation for the restriction of P. falciparum to its human host.surface plasmon resonance | protein interactions T he most deadly of the malaria parasites, Plasmodium falciparum, is highly divergent from the other species of Plasmodium known to infect humans (1-3), with its closest relatives comprising a group of chimpanzee and gorilla parasites from the subgenus Laverania (3-7). Despite the origin of P. falciparum as a zoonosis, and the continuing coexistence of humans and apes in West and Central Africa, extensive field studies have failed to detect P. falciparum in wild-living chimpanzees and gorillas (5). Although there are reports of P. falciparum infecting chimpanzees either in certain captive settings (2) or following splenectomy and deliberate transfer of P. falciparum-infected human blood (8-10), the resulting infections have low parasitemia and are not known to result in malignant tertian malaria, suggesting a host-specific barrier for replete infection. The existence of host-specific barriers within the Laverania subgenus is supported further by the strict host specificity exhibited by ape Laverania parasites in the wild: Plasmodium reichenowi, Plasmodium billcollinsi, and Plasmodium gaboni infect only chimpanzees, and Plasmodium praefalciparum, Plasmodium blacklocki, and Plasm...

Multiprotein complex between the GPI-anchored CyRPA with PfRH5 and PfRipr is crucial for Plasmodium falciparum erythrocyte invasion

“…This definitely was a great advancement, because previously such potent strain-transcending inhibition against multiple P. falciparum strains could not be demonstrated with leading essential blood-stage vaccine candidates (AMA-1, MSP-1). PfRH5 was also shown to be a major determinant of host cell tropism, which was first reported for P. falciparum invasion of Aotus nancymaae erythrocytes (5) and later for other species (8,26). Thus, PfRH5 emerged as an essential erythrocyte-binding protein that played a crucial role in erythrocyte invasion.…”

“…The quest to develop successful blood-stage malaria vaccines that efficiently block this process have focused on essential parasite proteins like merozoite surface protein 1 (MSP-1) and apical membrane antigen 1 (AMA-1); however, these are highly polymorphic, unable to elicit strain-transcending neutralizing antibodies, and have thus failed in field trials (4). Among the large repertoire of invasionrelated proteins, the family of P. falciparum reticulocyte bindinglike homologous (PfRH) proteins have emerged as key determinants of different invasion pathways (2,3), of which PfRH5 is the only essential conserved parasite ligand (5)(6)(7)(8) that elicits potent strain-transcending neutralizing antibodies (9)(10)(11)(12). It is localized in the rhoptry and secreted to the merozoite surface during erythrocyte invasion (6).…”

Lack of Association between BSG Polymorphisms and Cerebral Malaria

“…It has also been reported that PfRh5 binds chimpanzee BSG with a significantly lower affinity than human BSG, and that it does not bind gorilla BSG (4). These observations suggest that the PfRh5-BSG interaction plays important roles not only in erythrocyte invasion by P. falciparum but also in the host species preferences of P. falciparum.…”

Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions

“…RH5 is also essential (16,21) and forms a critical nonredundant interaction with its receptor basigin (CD147) on the RBC surface (22). Somewhat surprisingly, RH5 appears to be under relatively low-level immune pressure following natural infection (12,(23)(24)(25)(26), with functional constraints also linked to basigin binding and host RBC tropism (21,27,28) -both of these factors potentially explain its relatively high degree of sequence conservation. Recently, the N-terminal region of RH5 (RH5Nt) has been shown to bind the essential glycosylphosphatidylinositol-anchored (GPI-anchored) merozoite protein P113, providing a mechanism for anchoring RH5 to the merozoite surface (29).…”