Abstract
BackgroundChemotherapy can prompt the evolution of classical drug resistance, but selection can also favour other parasite traits that confer a survival advantage in the presence of drugs. The experiments reported here test the hypothesis that sub-optimal drug treatment of malaria parasites might generate survival and transmission advantages for virulent parasites.MethodsTwo Plasmodium chabaudi lines, one derived from the other by serial passage, were used to establish avirulent and virulent infections in mice. After five days, infections were treated with various doses of pyrimethamine administered over 1 or 4 days. Virulence measures (weight and anaemia), parasite and gametocyte dynamics were followed until day 21.ResultsAll treatment regimes reduced parasite and gametocyte densities, but infections with the virulent line always produced more parasites and more gametocytes than infections with the avirulent line. Consistent with our hypothesis, drug treatment was disproportionately effective against the less virulent parasites. Treatment did not affect the relative transmission advantage of the virulent line. Neither of the lines contained known mutations conferring classical drug resistance.ConclusionDrug-sensitivity of malaria parasites can be virulence-dependent, with virulent parasites more likely to survive sub-optimal treatment. If this proves to be general for a variety of drugs and parasite species, selection imposed by sub-optimal drug treatment could result in the evolution of more aggressive malaria parasites.
Highlights
Chemotherapy can prompt the evolution of classical drug resistance, but selection can favour other parasite traits that confer a survival advantage in the presence of drugs
If the virulent line is less sensitive to drug treatment, the reduction in parasite numbers will be disproportionately greater for the avirulent line (1B)
Cumulative asexual parasite density was reduced by drug treatment, but remained significantly higher in CWvir than CWavir infections (Figure 5; clone effect, F1,90 = 153.4, p < 0.0001)
Summary
Chemotherapy can prompt the evolution of classical drug resistance, but selection can favour other parasite traits that confer a survival advantage in the presence of drugs. Testing whether a given drug regime has differential effects on virulent and avirulent parasites is the first key step in testing the hypothesis that chemotherapy has the potential to impose selection for parasite traits other than those involved in classical resistance (Figure 1). Such selection processes may be occurring in the field but are difficult to study due to various confounding factors, including the presence of multiple, interbreeding parasite genotypes. In vivo experiments using an animal model were designed to test if sensitivity to drug treatment can be virulence-dependent
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