Chemotherapy, within-host ecology and the fitness of drug-resistant malaria parasites

Silvie Huijben, William A. Nelson, Andrew R. Wargo, Derek G. Sim, Damien R. Drew, Andrew F. Read

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

A major determinant of the rate at which drug-resistant malaria parasites spread through a population is the ecology of resistant and sensitive parasites sharing the same host. Drug treatment can significantly alter this ecology by removing the drug-sensitive parasites, leading to competitive release of resistant parasites. Here, we test the hypothesis that the spread of resistance can be slowed by reducing drug treatment and hence restricting competitive release. Using the rodent malaria model Plasmodium chabaudi, we found that low-dose chemotherapy did reduce competitive release. A higher drug dose regimen exerted stronger positive selection on resistant parasites for no detectable clinical gain. We estimated instantaneous selection coefficients throughout the course of replicate infections to analyze the temporal pattern of the strength and direction of within-host selection. The strength of selection on resistance varied through the course of infections, even in untreated infections, but increased immediately following drug treatment, particularly in the high-dose groups. Resistance remained under positive selection for much longer than expected from the half life of the drug. Although there are many differences between mice and people, our data do raise the question whether the aggressive treatment regimens aimed at complete parasite clearance are the best resistance-management strategies for humans.

Original languageEnglish (US)
Pages (from-to)2952-2968
Number of pages17
JournalEvolution
Volume64
Issue number10
DOIs
StatePublished - Oct 1 2010
Externally publishedYes

Fingerprint

chemotherapy
malaria
Ecology
Malaria
drug therapy
parasite
Parasites
drug
fitness
ecology
parasites
Drug Therapy
drugs
Pharmaceutical Preparations
dosage
Plasmodium chabaudi
infection
Infection
resistance management
host selection

Keywords

  • Competitive release
  • Plasmodium chabaudi
  • Selection coefficient
  • Transmission
  • Within-host fitness

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Agricultural and Biological Sciences(all)

Cite this

Chemotherapy, within-host ecology and the fitness of drug-resistant malaria parasites. / Huijben, Silvie; Nelson, William A.; Wargo, Andrew R.; Sim, Derek G.; Drew, Damien R.; Read, Andrew F.

In: Evolution, Vol. 64, No. 10, 01.10.2010, p. 2952-2968.

Research output: Contribution to journalArticle

Huijben, Silvie ; Nelson, William A. ; Wargo, Andrew R. ; Sim, Derek G. ; Drew, Damien R. ; Read, Andrew F. / Chemotherapy, within-host ecology and the fitness of drug-resistant malaria parasites. In: Evolution. 2010 ; Vol. 64, No. 10. pp. 2952-2968.
@article{96162073bc8e4cd08e7b2d7a213b83ba,
title = "Chemotherapy, within-host ecology and the fitness of drug-resistant malaria parasites",
abstract = "A major determinant of the rate at which drug-resistant malaria parasites spread through a population is the ecology of resistant and sensitive parasites sharing the same host. Drug treatment can significantly alter this ecology by removing the drug-sensitive parasites, leading to competitive release of resistant parasites. Here, we test the hypothesis that the spread of resistance can be slowed by reducing drug treatment and hence restricting competitive release. Using the rodent malaria model Plasmodium chabaudi, we found that low-dose chemotherapy did reduce competitive release. A higher drug dose regimen exerted stronger positive selection on resistant parasites for no detectable clinical gain. We estimated instantaneous selection coefficients throughout the course of replicate infections to analyze the temporal pattern of the strength and direction of within-host selection. The strength of selection on resistance varied through the course of infections, even in untreated infections, but increased immediately following drug treatment, particularly in the high-dose groups. Resistance remained under positive selection for much longer than expected from the half life of the drug. Although there are many differences between mice and people, our data do raise the question whether the aggressive treatment regimens aimed at complete parasite clearance are the best resistance-management strategies for humans.",
keywords = "Competitive release, Plasmodium chabaudi, Selection coefficient, Transmission, Within-host fitness",
author = "Silvie Huijben and Nelson, {William A.} and Wargo, {Andrew R.} and Sim, {Derek G.} and Drew, {Damien R.} and Read, {Andrew F.}",
year = "2010",
month = "10",
day = "1",
doi = "10.1111/j.1558-5646.2010.01068.x",
language = "English (US)",
volume = "64",
pages = "2952--2968",
journal = "Evolution; international journal of organic evolution",
issn = "0014-3820",
publisher = "Society for the Study of Evolution",
number = "10",

}

TY - JOUR

T1 - Chemotherapy, within-host ecology and the fitness of drug-resistant malaria parasites

AU - Huijben, Silvie

AU - Nelson, William A.

AU - Wargo, Andrew R.

AU - Sim, Derek G.

AU - Drew, Damien R.

AU - Read, Andrew F.

PY - 2010/10/1

Y1 - 2010/10/1

N2 - A major determinant of the rate at which drug-resistant malaria parasites spread through a population is the ecology of resistant and sensitive parasites sharing the same host. Drug treatment can significantly alter this ecology by removing the drug-sensitive parasites, leading to competitive release of resistant parasites. Here, we test the hypothesis that the spread of resistance can be slowed by reducing drug treatment and hence restricting competitive release. Using the rodent malaria model Plasmodium chabaudi, we found that low-dose chemotherapy did reduce competitive release. A higher drug dose regimen exerted stronger positive selection on resistant parasites for no detectable clinical gain. We estimated instantaneous selection coefficients throughout the course of replicate infections to analyze the temporal pattern of the strength and direction of within-host selection. The strength of selection on resistance varied through the course of infections, even in untreated infections, but increased immediately following drug treatment, particularly in the high-dose groups. Resistance remained under positive selection for much longer than expected from the half life of the drug. Although there are many differences between mice and people, our data do raise the question whether the aggressive treatment regimens aimed at complete parasite clearance are the best resistance-management strategies for humans.

AB - A major determinant of the rate at which drug-resistant malaria parasites spread through a population is the ecology of resistant and sensitive parasites sharing the same host. Drug treatment can significantly alter this ecology by removing the drug-sensitive parasites, leading to competitive release of resistant parasites. Here, we test the hypothesis that the spread of resistance can be slowed by reducing drug treatment and hence restricting competitive release. Using the rodent malaria model Plasmodium chabaudi, we found that low-dose chemotherapy did reduce competitive release. A higher drug dose regimen exerted stronger positive selection on resistant parasites for no detectable clinical gain. We estimated instantaneous selection coefficients throughout the course of replicate infections to analyze the temporal pattern of the strength and direction of within-host selection. The strength of selection on resistance varied through the course of infections, even in untreated infections, but increased immediately following drug treatment, particularly in the high-dose groups. Resistance remained under positive selection for much longer than expected from the half life of the drug. Although there are many differences between mice and people, our data do raise the question whether the aggressive treatment regimens aimed at complete parasite clearance are the best resistance-management strategies for humans.

KW - Competitive release

KW - Plasmodium chabaudi

KW - Selection coefficient

KW - Transmission

KW - Within-host fitness

UR - http://www.scopus.com/inward/record.url?scp=78649239551&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78649239551&partnerID=8YFLogxK

U2 - 10.1111/j.1558-5646.2010.01068.x

DO - 10.1111/j.1558-5646.2010.01068.x

M3 - Article

C2 - 20584075

AN - SCOPUS:78649239551

VL - 64

SP - 2952

EP - 2968

JO - Evolution; international journal of organic evolution

JF - Evolution; international journal of organic evolution

SN - 0014-3820

IS - 10

ER -