title: A murine model of falciparum-malaria by in vivo selection of competent strains in non-myelodepleted mice engrafted with human erythrocytes.
abstract: To counter the global threat caused by Plasmodium falciparum malaria, new drugs and vaccines are urgently needed. However, there are no practical animal models because P. falciparum infects human erythrocytes almost exclusively. Here we describe a reliable falciparum murine model of malaria by generating strains of P. falciparum in vivo that can infect immunodeficient mice engrafted with human erythrocytes. We infected NOD(scid/beta2m-/-) mice engrafted with human erythrocytes with P. falciparum obtained from in vitro cultures. After apparent clearance, we obtained isolates of P. falciparum able to grow in peripheral blood of engrafted NOD(scid/beta2m-/-) mice. Of the isolates obtained, we expanded in vivo and established the isolate Pf3D7(0087/N9) as a reference strain for model development. Pf3D7(0087/N9) caused productive persistent infections in 100% of engrafted mice infected intravenously. The infection caused a relative anemia due to selective elimination of human erythrocytes by a mechanism dependent on parasite density in peripheral blood. Using this model, we implemented and validated a reproducible assay of antimalarial activity useful for drug discovery. Thus, our results demonstrate that P. falciparum contains clones able to grow reproducibly in mice engrafted with human erythrocytes without the use of myeloablative methods.
authors.affiliation: Diseases of the Developing World, Infectious Diseases-Centre for Excellence in Drug Discovery, GlaxoSmithKline, Tres Cantos, Madrid, Spain. inigo.x.angulo@gsk.com
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.forename: María Belén
authors.initials: MB
authors.lastname: Jiménez-Díaz
authors.forename: Teresa
authors.initials: T
authors.lastname: Mulet
authors.forename: Joaquín
authors.initials: J
authors.lastname: Rullas
authors.forename: Esperanza
authors.initials: E
authors.lastname: Herreros
authors.forename: Santiago
authors.initials: S
authors.lastname: Ferrer
authors.forename: Elena
authors.initials: E
authors.lastname: Jiménez
authors.forename: Alfonso
authors.initials: A
authors.lastname: Mendoza
authors.forename: Javier
authors.initials: J
authors.lastname: Regadera
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Ian
authors.initials: I
authors.lastname: Bathurst
authors.forename: David L
authors.initials: DL
authors.lastname: Pompliano
authors.forename: Federico
authors.initials: F
authors.lastname: Gómez de las Heras
authors.forename: Domingo
authors.initials: D
authors.lastname: Gargallo-Viola
mesh_terms: D000818:Animals; D017707:Erythrocyte Transfusion; D006801:Humans; D016778:Malaria, Falciparum / Q000097:blood*; D051379:Mice; D016688:Mice, Inbred NOD; D010963:Plasmodium falciparum / Q000254:growth & development; D014183:Transplantation, Heterologous