Resurrection of the ancestral RH5 invasion ligand provides a molecular explanation for the origin of P. falciparum malaria in humans.

Francis Galaway,Ryan Yu,Franck Prugnolle,Gavin J Wright,Anastasia Constantinou,Andrew Fraser Read

doi:10.1371/journal.pbio.3000490

Abstract

Many important infectious diseases are the result of zoonoses, in which pathogens that normally infect animals acquire mutations that enable the breaching of species barriers to permit the infection of humans. Our understanding of the molecular events that enable host switching are often limited, and yet this is a fundamentally important question. Plasmodium falciparum, the etiological agent of severe human malaria, evolved following a zoonotic transfer of parasites from gorillas. One gene-rh5-which encodes an essential ligand for the invasion of host erythrocytes, is suspected to have played a critical role in this host switch. Genome comparisons revealed an introgressed sequence in the ancestor of P. falciparum containing rh5, which likely allowed the ancestral parasites to infect both gorilla and human erythrocytes. To test this hypothesis, we resurrected the ancestral introgressed reticulocyte-binding protein homologue 5 (RH5) sequence and used quantitative protein interaction assays to demonstrate that this ancestral protein could bind the basigin receptor from both humans and gorillas. We also showed that this promiscuous receptor binding phenotype of RH5 was shared with the parasite clade that transferred its genome segment to the ancestor of P. falciparum, while the other lineages exhibit host-specific receptor binding, confirming the central importance of this introgression event for Plasmodium host switching. Finally, since its transfer to humans, P. falciparum, and also the RH5 ligand, have evolved a strong human specificity. We show that this subsequent restriction to humans can be attributed to a single amino acid mutation in the RH5 sequence. Our findings reveal a molecular pathway for the origin and evolution of human P. falciparum malaria and may inform molecular surveillance to predict future zoonoses.

Highlights

The majority of emerging infectious diseases are zoonotic and arise by the acquisition of mutations that permit the infection of humans [1]
The discovery that the origins of P. falciparum are the Laverania has raised questions of what determines the strict tropism of these parasites for their gorilla and chimpanzee hosts, and, perhaps more importantly, what were the molecular changes that permitted the zoonotic infection of humans
Anecdotal observations suggesting a molecular restriction factor in the blood stages [23], the identification of an introgression event encoding the essential invasion ligand reticulocyte-binding protein homologue 5 (RH5) [8,9,16], and the specificity of P. falciparum RH5 binding to human, but not gorilla or chimpanzee basigin [21], all implicated a role for this host–parasite receptor–ligand interaction; the molecular pathway triggering the zoonotic infection of humans was unknown

Summary

Introduction

The majority of emerging infectious diseases are zoonotic and arise by the acquisition of mutations that permit the infection of humans [1]. A molecular pathway for the origin of Plasmodium falciparum malaria inability of P. falciparum RH5 to bind gorilla and only weakly to chimpanzee basigin suggested the RH5–basigin interaction was responsible for the restriction of P. falciparum to humans [21]. It was widely thought, that host restriction in Laveranian parasites was determined by the specificity of the RH5–basigin interaction and that the transfer of this gene from P. adleri into the ancestor of P. falciparum/P. praefalciparum was the founding event leading to the evolution of one of the most deadly human parasites, P. falciparum [8]. We demonstrate that a single residue in RH5 can explain the subsequent restriction of P. falciparum to humans, thereby revealing a molecular pathway for the zoonotic origin of P. falciparum malaria

Results

Discussion

Materials and methods