Various PfRH5 polymorphisms can support Plasmodium falciparum invasion into the erythrocytes of owl monkeys and rats

Abstract

Aotus nancymaae, the owl monkey, provides a useful laboratory model for research to develop drugs and vaccines against human falciparum malaria; however, many Plasmodium falciparum parasites are unable to invade A. nancymaae erythrocytes, rendering the parasites noninfective to the monkeys. In previous work, we identified a key polymorphism that determined the inheritance of erythrocyte invasion in a genetic cross of two P. falciparum clones that were virulent (GB4) or noninfective (7G8) to A. nancymaae. This polymorphism, an isoleucine-to-lysine polymorphism at position 204 (I204K) of the GB4 erythrocyte binding protein PfRH5, was nevertheless not found in several other P. falciparum lines that could also invade A. nancymaae erythrocytes. Alternative PfRH5 polymorphisms occur at different positions in these virulent parasites, and additional polymorphisms are found in P. falciparum parasites that cannot infect A. nancymaae. By allelic replacement methods, we have introduced the polymorphisms of these A. nancymaae-virulent or noninfective parasites at codons 204, 347, 358, 362, 410, and 429 of the endogenous PfRH5 gene in the noninfective 7G8 line. 7G8 transformants expressing the polymorphisms of the A. nancymaae-virulent parasites show neuraminidase-sensitive (sialic acid-dependent) invasion into the monkey erythrocytes, whereas 7G8 transformants expressing the PfRH5 alleles of noninfective parasites show little or no invasion of these erythrocytes. Parasites harboring PfRH5 polymorphisms 204K or 204R are also able to invade rat erythrocytes and are differentially sensitive to the removal of surface sialic acids by neuraminidase. These studies offer insights into the PfRH5 receptor-binding domain and interactions that support the invasion of various primate and rodent erythrocytes by P. falciparum.

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

“…It also is known that a lower affinity of the PfRH5-BSG interaction can adversely affect P. falciparum erythrocyte invasion, because Ok a− blood group erythrocytes, which carry a homozygous BSG polymorphism that binds PfRH5 with a twofold-lower affinity, are not invaded as efficiently as Ok a+ erythrocytes (28). Finally, these findings concur with the identification of PfRH5 variants that are responsible for the species selectivity of P. falciparum in both owl monkeys (Aotus nancymaae) and rats (26,27). Thus, several lines of evidence suggest that the PfRH5-BSG interaction is a major determinant of host species tropism.…”

“…Therefore there is reasonable doubt about the importance of the EBA175-GYPA interaction in Laverania host tropism. A second and unrelated invasion ligand, Plasmodium falciparum Reticulocytebinding protein homolog 5 (PfRH5) has also been implicated in host tropism by governing the ability of P. falciparum to infect New World Aotus monkeys (26,27). The erythrocyte cell-surface receptor of PfRH5, Basigin (BSG), was identified only recently (28), and so the contribution of the PfRH5-BSG interaction toward determining host-species selectivity in P. falciparum is unknown.…”

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.…”

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).…”