Adaptation_of_Plasmodium_falciparum_to_humans_involved_the_loss_of_an_ape_specific_erythrocyte_invasion_ligand. Adaptation_of_Plasmodium_falciparum_to_humans_involved_the_loss_of_an_ape_specific_erythrocyte_invasion_ligand

Plasmodium is a highly successful genus of single-celled parasites that have evolved to infect most terrestrial vertebrate families. Individual species are generally highly host specific, but little is currently known about the molecular factors that restrict Plasmodium species to specific vertebrate hosts. This is particularly relevant in the case of P. falciparum, which still kills nearly half a million individuals every year. It is now known that P. falciparum is the only human-infective species of a sub-genus of at least eight species, collectively referred to as Laverania, where all other members infect African apes. The cross-species transfer of an ape-infective Plasmodium precursor to humans was clearly a critical moment in the evolution of our species, but the precise steps required for that event are unknown. Genes associated with the recognition and invasion of erythrocytes are amongst the most variable between Laverania species, and here we show that all P. falciparum isolates sequenced to date contain an inactivating mutation in a single invasion associated gene, PfEBA165, while the corresponding gene encodes an intact reading frame in all ape-infective Laverania species. Biochemical studies showed that the corresponding proteins bound ape erythrocytes, but were unable to recognise human erythrocytes. This was found to be due to variation in the sialic acids expressed on the different erythrocyte surfaces of human and ape erythrocytes. Correction of the inactivating mutation by CRISPR-Cas9 genome editing in P. falciparum yielded viable parasites, but was concomitant with the the near-complete down regulation of PfEBA165 transcription, suggesting that expression of an intact PfEBA165 protein is incompatible with efficient parasite growth in human erythrocytes. These data suggest that the pseudogenization of PfEBA165 represented a key step in the emergence and evolution of P. falciparum into a successful human-infective species, and that an intact PfEBA165 gene represents a major barrier to Laverania cross-species transmission. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/