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 NODscid/β2m−/− 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 NODscid/β2m−/− mice. Of the isolates obtained, we expanded in vivo and established the isolate Pf3D70087/N9 as a reference strain for model development. Pf3D70087/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.
Highlights
The erythrocytic stages of the most virulent human malaria parasite, P. falciparum, are responsible for hundreds of millions of illnesses and over one million deaths every year [1]
The human erythrocytes (hE) suspension contained human serum and hypoxanthine because human serum increases the half life of engrafted hE [7] and both components might enhance the growth of P. falciparum
According to our results, P. vinckei would be a better surrogate of P. falciparum than P. berghei for testing in vivo diamidine derivatives. These results suggested that the falciparum murine model of malaria might be used to select surrogate standard rodent models that had better correlation with P. falciparum when testing in vivo new families of compounds
Summary
The erythrocytic stages of the most virulent human malaria parasite, P. falciparum, are responsible for hundreds of millions of illnesses and over one million deaths every year [1]. A reliable murine model of P. falciparum malaria would be a valuable research tool, in drug discovery [6] At least, such a model should guarantee that the parasite grows in a predictable way in peripheral blood of mice having circulating human erythrocytes (hE) in bloodstream, the physiologically relevant compartment. The different versions of this model require intraperitoneal infection, have a high rate of failure [8,9,13] or show limited reproducibility of infection outcome [10,11], display variable kinetics of parasitemia, and use toxic reagents, which might interact in unknown ways with antimalarials or effector cells These shortcomings have limited its use in drug discovery [3] and vaccine development, despite several standard antimalarials [9] and antibodies [13,14,15] were shown to have activity in this model
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