Explorer 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. Conclusion: 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. Background Patients in endemic areas often carry malaria parasites while having levels of antimalarial drugs in their blood that fail to eliminate all parasites. This can be due to the presence of residual levels of drugs when a new infection is acquired [1,2], because recommended treatment could not clear all parasites [3-6] or because of inadequate treatment (for example from low quality drugs [7,8] or poor compliance). Due to variable metabolic drug uptake [9,10], recommended doses may not be adequate for all sub-groups, such as children or pregnant women [4,11,12]. Even during supervised treatment with potent and high quality drugs, including artemisinin-based combination therapies, patients can be cured from disease Published: 16 December 2008 Malaria Journal 2008, 7:257 doi:10.1186/1475-2875-7-257 Received: 6 August 2008 Accepted: 16 December 2008 This article is available from: http://www.malariajournal.com/content/7/1/257 © 2008 Schneider et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Malaria Journal 2008, 7:257 http://www.malariajournal.com/content/7/1/257