Does the drug sensitivity of malaria parasites depend on their virulence?
BACKGROUND
Chemotherapy 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.


METHODS
Two 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.


RESULTS
All 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.


CONCLUSIONS
Drug-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.
Schneider
Petra
P
Institutes of Evolution, Immunology and Infection Research, University of Edinburgh, EH9 3JT, UK. petra.schneider@ed.ac.uk
Chan
Brian Hk
BH
Reece
Sarah E
SE
Read
Andrew F
AF
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D002488:Central African Republic; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005838:Genotype; D051379:Mice; D021261:Parasitic Sensitivity Tests; D016788:Plasmodium chabaudi / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D011739:Pyrimethamine / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014774:Virulence / Q000235:genetics*
D000962:Antimalarials; D011739:Pyrimethamine