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

Proceedings of the National Academy of Sciences of the United States of America

By:
, , , , and
DOI: 10.1073/pnas.0707766104

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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. ?? 2007 by The National Academy of Sciences of the USA.

Additional Publication Details

Publication type:
Article
Publication Subtype:
Journal Article
Title:
Competitive release and facilitation of drug-resistant parasites after therapeutic chemotherapy in a rodent malaria model
Series title:
Proceedings of the National Academy of Sciences of the United States of America
DOI:
10.1073/pnas.0707766104
Volume
104
Issue:
50
Year Published:
2007
Language:
English
Larger Work Type:
Article
Larger Work Subtype:
Journal Article
Larger Work Title:
Proceedings of the National Academy of Sciences of the United States of America
First page:
19914
Last page:
19919
Number of Pages:
6