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

by Francis Galaway, Ryan Yu, Anastasia Constantinou, Franck Prugnolle, Gavin J. Wright

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 ofP.falciparum containingrh5, 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 ofP.falciparum, while the other lineages exhibit host-specific receptor binding, confirming the central importance of this introgression event f...

Source: PLoS Biology: Archived Table of Contents - October 14, 2019 Category: Biology Authors: Francis Galaway Source Type: research