1. A murine model of falciparum-malaria by in vivo selection of competent strains in non-myelodepleted mice engrafted with human erythrocytes
- Author
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Philip J. Rosenthal, María Belén Jiménez-Díaz, Teresa Mulet, David L. Pompliano, Domingo Gargallo-Viola, Ian Bathurst, Iñigo Angulo-Barturen, Alfonso Mendoza, Santiago Ferrer, Elena Jimenez, Javier Regadera, Federico Gómez de las Heras, Joaquín Rullas, Esperanza Herreros, and Keiser, Jennifer
- Subjects
Immunology/Immunomodulation ,lcsh:Medicine ,Microbiology/Innate Immunity ,Parasitemia ,Plasmodium ,Mice ,Mice, Inbred NOD ,Stem Cell Research - Nonembryonic - Human ,2.2 Factors relating to the physical environment ,2.1 Biological and endogenous factors ,Microbiology/Parasitology ,Malaria, Falciparum ,Aetiology ,lcsh:Science ,Heterologous ,Multidisciplinary ,biology ,Pharmacology/Drug Interactions ,Infectious Diseases ,Human erythrocytes ,HIV/AIDS ,Infection ,Erythrocyte Transfusion ,Research Article ,Infectious Diseases/Tropical and Travel-Associated Diseases ,Biotechnology ,Falciparum ,General Science & Technology ,Transplantation, Heterologous ,Immunology ,Plasmodium falciparum ,Rare Diseases ,In vivo ,parasitic diseases ,medicine ,Animals ,Humans ,Transplantation ,lcsh:R ,Infectious Diseases/Protozoal Infections ,Pharmacology/Drug Resistance ,biology.organism_classification ,medicine.disease ,Stem Cell Research ,Virology ,In vitro ,Malaria ,Vector-Borne Diseases ,Orphan Drug ,Infectious Diseases/Neglected Tropical Diseases ,Murine model ,Inbred NOD ,lcsh:Q ,Pharmacology/Drug Development - 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.
- Published
- 2008