Within host ecology: The evolution of drug resistance in malarial parasites in immunosuppressed hosts

Background/Question/Methods  Both malaria and HIV-infection account for significant worldwide mortality. In areas where both diseases are common, their interaction may influence their evolution. In sub-Saharan Africa, evidence suggests that HIV-infected individuals are more likely to harbor antimalarial-drug resistant strains of malaria than non-HIV infected individuals resulting in the potential for increased rate of spread of drug resistance. Here we conducted an experiment using mice infected with two strains of Plasmodium chabaudi, one pyrimethamine sensitive and one pyrimethamine resistant, to test the hypothesis that immunosuppression selects for greater antimalarial drug resistance. Four treatments consisted of immune intact mice not treated with antimalarial drugs, CD4+ T cell-depleted mice not treated with drugs, immune intact mice treated with pyrimethamine, and CD4+ T cell-depleted mice treated with pyrimethamine. Mouse weight, anemia, and the concentrations of sensitive and resistant parasite strains (both asexual and gametocyte stages) were monitored over the course of the experiment.

Results/Conclusions  Pyrimethamine treatment resulted in higher concentrations of the resistant strain of the parasite in both immune intact and immunosuppressed mice. Immunosuppression resulted in higher overall parasite loads in both drug-treated and non-drug treated mice. Drug treated, CD4+ T cell-depleted mice showed two different patterns in concentrations of sensitive and resistant parasites over time suggesting that the absence of an immune system may result in sensitivity to small variations in drug concentration or other variables. These results suggest that drug dosage levels may be important in determining if immunosuppressed individuals carry higher resistant parasite loads than immune-intact individuals. Alternative hypothesis are discussed.