Human malaria in immunocompromised mice: new in vivo model for chemotherapy studies

Abstract

We have recently designed a new Plasmodium falciparum mouse model and documented its potential for the study of immune effector mechanisms. In order to determine its value for drug studies, we evaluated its response to existing antimalarial drugs compared to that observed in humans. Immunocompromised BXN (bg/bg xid/xid nu/nu) mice were infected with either the sensitive NF54 strain or the multiresistant T24 strain and then treated with chloroquine, quinine, mefloquine, or dihydroartemisinin. A parallelism was observed between previously reported human responses and P. falciparum-parasitized human red blood cell (huRBC)--BXN mouse responses to classical antimalarial drugs, measured in terms of speed of decrease in parasitemia and of morphological alterations of the parasites. Mice infected with the sensitive strain were successfully cured after treatment with either chloroquine or mefloquine. In contrast, mice infected with the multiresistant strain failed to be cured by chloroquine or quinine but thereafter responded to dihydroartemisinin treatment. The speed of parasite clearance and the morphological alterations induced differed for each drug and matched previously reported observations, hence stressing the relevance of the model. These data thus suggest that P. falciparum-huRBC-BXN mice can provide a valuable in vivo system and should be included in the short list of animals that can be used for the evaluation of P. falciparum responses to drugs.

FIG. 1

Evolution of P. falciparum parasitemia in seven untreated mice. Mice were inoculated i.p. with 1 ml of highly synchronized cultures of P. falciparum at the ring stage on day 0. After infection, mice received normal RBC every 3 to 4 days. Parasitemia in mice was expressed as the percentage of P. falciparum-huRBC in the total RBC observed in thin smears. The data shown are from the first day of detectable parasitemia up to the day the mice were used for other malaria studies.

FIG. 2

Evolution of parasitemia in P. falciparum-infected mice before (continuous line) and after (discontinuous line) antimalarial treatment. Open symbols indicate the days of treatment. (A) Chloroquine was administered to three mice at a dose of 73 mg/kg on the first 2 days of treatment and at 36.5 mg/kg on the last day. (B) Mefloquine was administered to two mice at a dose of 50 mg/kg. (C) After failed chloroquine treatment (closed arrows) of two mice, they were treated with dihydroartemisinin (open arrows) at 50 mg/kg. (D) Quinine at 73 mg/kg was administered three times per day to two mice.

FIG. 3

Morphological changes induced in vivo by chloroquine, mefloquine, and dihydroartemisinin (DH-Artemisinine) in multiresistant strain T24 and sensitive strain NF54.