title: Pathogenicity Determinants of the Human Malaria ParasitePlasmodium falciparumHave Ancient Origins.
abstract: Plasmodium falciparum, the most deadly of the human malaria parasites, is a member of theLaveraniasubgenus that also infects African Great Apes. The virulence ofP. falciparumis related to cytoadhesion of infected erythrocytes in microvasculature, but the origin of dangerous parasite adhesion traits is poorly understood. To investigate the evolutionary history of theP. falciparumcytoadhesion pathogenicity determinant, we studied adhesion domains from the chimpanzee malaria parasiteP. reichenowi. We demonstrate that theP. reichenowi vargene repertoire encodes cysteine-rich interdomain region (CIDR) domains which bind human CD36 and endothelial protein C receptor (EPCR) with the same levels of affinity and at binding sites similar to those bound byP. falciparum. Moreover,P. reichenowidomains interfere with the protective function of the activated protein C-EPCR pathway on endothelial cells, a presumptive virulence trait in humans. These findings provide evidence for ancient evolutionary origins of two key cytoadhesion properties ofP. falciparumthat contribute to human infection and pathogenicity.IMPORTANCECytoadhesion ofP. falciparum-infected erythrocytes in the microcirculation is a major virulence determinant.P. falciparumis descended from a subgenus of parasites that also infect chimpanzees and gorillas and exhibits strict host species specificity. Despite their high genetic similarity toP. falciparum, it is unknown whether ape parasites encode adhesion properties similar to those ofP. falciparumor are as virulent in their natural hosts. Consequently, it has been unclear when virulent adhesion traits arose inP. falciparumand how long they have been present in the parasite population. It is also unknown whether cytoadhesive interactions pose a barrier to cross-species transmission. We show that parasite domains from the chimpanzee malaria parasiteP. reichenowibind human receptors with specificity similar to that ofP. falciparum. Our findings suggest that parasite adhesion traits associated with both mild and severe malaria have much earlier origins than previously appreciated and have important implications for virulence evolution in a major human pathogen.
authors.affiliation: Center for Infectious Disease Research, Seattle, Washington, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Brazier
authors.affiliation: Center for Infectious Disease Research, Seattle, Washington, USA.
authors.forename: Marion
authors.initials: M
authors.lastname: Avril
authors.affiliation: Center for Infectious Disease Research, Seattle, Washington, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Bernabeu
authors.affiliation: Center for Infectious Disease Research, Seattle, Washington, USA.
authors.forename: Maxwell
authors.initials: M
authors.lastname: Benjamin
authors.affiliation: Center for Infectious Disease Research, Seattle, Washington, USA; Department of Global Health, University of Washington, Seattle, Washington, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Smith
keywords: Plasmodium falciparum; Plasmodium reichenowi; cytoadhesion; var gene