title: A Novel Erythrocyte Binding Protein of Plasmodium vivax Suggests an Alternate Invasion Pathway into Duffy-Positive Reticulocytes.
abstract: Erythrocyte invasion by malaria parasites is essential for blood-stage development and an important determinant of host range. In Plasmodium vivax, the interaction between the Duffy binding protein (DBP) and its cognate receptor, the Duffy antigen receptor for chemokines (DARC), on human erythrocytes is central to blood-stage infection. Contrary to this established pathway of invasion, there is growing evidence of P. vivax infections occurring in Duffy blood group-negative individuals, suggesting that the parasite might have gained an alternative pathway to infect this group of individuals. Supporting this concept, a second distinct erythrocyte binding protein (EBP2), representing a new member of the DBP family, was discovered in P. vivax and may be the ligand in an alternate invasion pathway. Our study characterizes this novel ligand and determines its potential role in reticulocyte invasion by P. vivax merozoites. EBP2 binds preferentially to young (CD71(high)) Duffy-positive (Fy(+)) reticulocytes and has minimal binding capacity for Duffy-negative reticulocytes. Importantly, EBP2 is antigenically distinct from DBP and cannot be functionally inhibited by anti-DBP antibodies. Consequently, our results do not support EBP2 as a ligand for invasion of Duffy-negative blood cells, but instead, EBP2 may represent a novel ligand for an alternate invasion pathway of Duffy-positive reticulocytes.
  
  
  
  For decades, P. vivax infections in humans have been defined by a unique requirement for the interaction between the Duffy binding protein ligand of the parasite and the Duffy blood group antigen receptor (DARC). Recent reports of P. vivax infections in Duffy-negative individuals challenge this paradigm and suggest an alternate pathway of infection, potentially using the recently discovered EBP2. However, we demonstrate that EBP2 host cell specificity is more restricted than DBP binding and that EBP2 binds preferentially to Duffy-positive, young reticulocytes. This finding indicates that this DBP paralog does mediate a Duffy-independent pathway of infection.
authors.affiliation: Center for Global Health and Infectious Diseases Research, College of Public Health, University of South Florida, Tampa, Florida, USA fntumngi@health.usf.edu usfmalaria@gmail.com.
authors.forename: Francis B
authors.initials: FB
authors.lastname: Ntumngia
authors.affiliation: Center for Global Health and Infectious Diseases Research, College of Public Health, University of South Florida, Tampa, Florida, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Thomson-Luque
authors.affiliation: Center for Global Health and Infectious Diseases Research, College of Public Health, University of South Florida, Tampa, Florida, USA Centro de Pesquisas René Rachou/FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Letícia de Menezes
authors.initials: Lde M
authors.lastname: Torres
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Karthigayan
authors.initials: K
authors.lastname: Gunalan
authors.affiliation: Centro de Pesquisas René Rachou/FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Luzia H
authors.initials: LH
authors.lastname: Carvalho
authors.affiliation: Center for Global Health and Infectious Diseases Research, College of Public Health, University of South Florida, Tampa, Florida, USA fntumngi@health.usf.edu usfmalaria@gmail.com.
authors.forename: John H
authors.initials: JH
authors.lastname: Adams
mesh_terms: D000913:Antibodies, Protozoan / Q000276:immunology; D015703:Antigens, CD / Q000032:analysis; D000953:Antigens, Protozoan / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D004375:Duffy Blood-Group System / Q000032:analysis; D006801:Humans; D010966:Plasmodium vivax / Q000502:physiology*; D015800:Protozoan Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000032:analysis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D011990:Receptors, Transferrin / Q000032:analysis; D012156:Reticulocytes / Q000737:chemistry* / Q000469:parasitology*
chemical_list: C473745:ACKR1 protein, human; D000913:Antibodies, Protozoan; D015703:Antigens, CD; D000953:Antigens, Protozoan; C068126:CD71 antigen; D004375:Duffy Blood-Group System; C066001:Duffy antigen binding protein, Plasmodium; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; D011990:Receptors, Transferrin