Competitive release and facilitation of drug-resistant parasites after therapeutic chemotherapy in a rodent malaria model

doi:10.1073/pnas.0707766104

Competitive release and facilitation of drug-resistant parasites after therapeutic chemotherapy in a rodent malaria model

*Institutes of Evolutionary Biology and Immunology and Infection Research, Ashworth Laboratories, School of Biological Science, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, United Kingdom;
^§US Geological Survey, Western Fisheries Research Center, 6505 NE 65^th Street, Seattle, WA 98115-5016;
^†School of Public Health and Community Medicine, University of Washington, Box 357238, Seattle, WA 98195;
^¶Biology Department, Emory University, 1510 Clifton Road, Atlanta, GA 30322; and
^‖Center for Infectious Disease Dynamics, Departments of Biology and Entomology, 208 Mueller Laboratory, Pennsylvania State University, University Park, PA 16802

Edited by Daniel L. Hartl, Harvard University, Cambridge, MA, and approved October 18, 2007 (received for review August 17, 2007)

Abstract

Malaria infections frequently consist of mixtures of drug-resistant and drug-sensitive parasites. If crowding occurs, where clonal population densities are suppressed by the presence of coinfecting clones, removal of susceptible clones by drug treatment could allow resistant clones to expand into the newly vacated niche space within a host. Theoretical models show that, if such competitive release occurs, it can be a potent contributor to the strength of selection, greatly accelerating the rate at which resistance spreads in a population. A variety of correlational field data suggest that competitive release could occur in human malaria populations, but direct evidence cannot be ethically obtained from human infections. Here we show competitive release after pyrimethamine curative chemotherapy of acute infections of the rodent malaria Plasmodium chabaudi in laboratory mice. The expansion of resistant parasite numbers after treatment resulted in enhanced transmission-stage densities. After the elimination or near-elimination of sensitive parasites, the number of resistant parasites increased beyond that achieved when a competitor had never been present. Thus, a substantial competitive release occurred, markedly elevating the fitness advantages of drug resistance above those arising from survival alone. This finding may explain the rapid spread of drug resistance and the subsequently brief useful lifespans of some antimalarial drugs. In a second experiment, where subcurative chemotherapy was administered, the resistant clone was only partly released from competitive suppression and experienced a restriction in the size of its expansion after treatment. This finding raises the prospect of harnessing in-host ecology to slow the spread of drug resistance.

Footnotes

^‡To whom correspondence should be addressed. E-mail: awargo{at}u.washington.edu
Author contributions: A.R.W., S.H., J.C.d.R., J.S., and A.F.R. designed research; A.R.W., S.H., J.C.d.R., and J.S. performed research; A.R.W. and A.F.R. contributed new reagents/analytic tools; A.R.W. analyzed data; and A.R.W. and A.F.R. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Freely available online through the PNAS open access option.