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Abstract
Background Plasmodium vivax is the most prevalent human malaria parasite, causing serious public health problems in malaria-endemic countries. Until recently the Duffy-negative blood group phenotype was considered to confer resistance to vivax malaria for most African ethnicities. We and others have reported that P. vivax strains in African countries from Madagascar to Mauritania display capacity to cause clinical vivax malaria in Duffy-negative people. New insights must now explain Duffy-independent P. vivax invasion of human erythrocytes.Methods/Principal FindingsThrough recent whole genome sequencing we obtained ≥70× coverage of the P. vivax genome from five field-isolates, resulting in ≥93% of the Sal I reference sequenced at coverage greater than 20×. Combined with sequences from one additional Malagasy field isolate and from five monkey-adapted strains, we describe here identification of DNA sequence rearrangements in the P. vivax genome, including discovery of a duplication of the P. vivax Duffy binding protein (PvDBP) gene. A survey of Malagasy patients infected with P. vivax showed that the PvDBP duplication was present in numerous locations in Madagascar and found in over 50% of infected patients evaluated. Extended geographic surveys showed that the PvDBP duplication was detected frequently in vivax patients living in East Africa and in some residents of non-African P. vivax-endemic countries. Additionally, the PvDBP duplication was observed in travelers seeking treatment of vivax malaria upon returning home. PvDBP duplication prevalence was highest in west-central Madagascar sites where the highest frequencies of P. vivax-infected, Duffy-negative people were reported.Conclusions/SignificanceThe highly conserved nature of the sequence involved in the PvDBP duplication suggests that it has occurred in a recent evolutionary time frame. These data suggest that PvDBP, a merozoite surface protein involved in red cell adhesion is rapidly evolving, possibly in response to constraints imposed by erythrocyte Duffy negativity in some human populations.
Highlights
Merozoite contact and tight junction formation with the red blood cell (RBC) initiate the cycle of events that result in human malaria [1]
The events governed by DBP-Duffy antigen interaction were shown to fail when P. knowlesi merozoites were allowed to interact with Duffy-negative human RBCs [5], and subsequently when P. knowlesi DBP knockout mutants were allowed to interact with Duffy-positive human RBCs [6]
Analyses based solely on sequence coverage are further complicated in patient samples by the presence of multiple parasite strains [14]: if a locus is deleted in a strain that accounts for 10% of the parasites in the blood, the sequence coverage would only decrease by 10% and be difficult to identify
Summary
Merozoite contact and tight junction formation with the red blood cell (RBC) initiate the cycle of events that result in human malaria [1] Evidence that these events require specific molecular interactions was revealed through in vitro and in vivo studies demonstrating that P. knowlesi and the highly prevalent, human parasite, P. vivax were unable to cause infection of RBCs that did not express the Duffy blood group antigen [2,3]. With these observations and advent of molecular biological methods, the first of the so-called malaria parasite invasion ligands identified was the P. knowlesi Duffy binding protein that is expressed in the micronemes located at the merozoite apex [4]. New insights must explain Duffy-independent P. vivax invasion of human erythrocytes
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