Within-host competition and drug resistance in the human malaria parasite Plasmodium falciparum.

Mary Bushman,Benjamin Abuaku,Peter Lyaruu,Neils Quashie,Nancy Duah,Jacobus C De Roode,Venkatachalam Udhayakumar,Pedro Rafael Dimbu,S Patrick Kachur,Mateusz Plucinski,Julie Gutman,Lindsay Morton,Kwadwo A Koram

doi:10.1098/rspb.2015.3038

Abstract

Infections with the malaria parasite Plasmodium falciparum typically comprise multiple strains, especially in high-transmission areas where infectious mosquito bites occur frequently. However, little is known about the dynamics of mixed-strain infections, particularly whether strains sharing a host compete or grow independently. Competition between drug-sensitive and drug-resistant strains, if it occurs, could be a crucial determinant of the spread of resistance. We analysed 1341 P. falciparum infections in children from Angola, Ghana and Tanzania and found compelling evidence for competition in mixed-strain infections: overall parasite density did not increase with additional strains, and densities of individual chloroquine-sensitive (CQS) and chloroquine-resistant (CQR) strains were reduced in the presence of competitors. We also found that CQR strains exhibited low densities compared with CQS strains (in the absence of chloroquine), which may underlie observed declines of chloroquine resistance in many countries following retirement of chloroquine as a first-line therapy. Our observations support a key role for within-host competition in the evolution of drug-resistant malaria. Malaria control and resistance-management efforts in high-transmission regions may be significantly aided or hindered by the effects of competition in mixed-strain infections. Consideration of within-host dynamics may spur development of novel strategies to minimize resistance while maximizing the benefits of control measures.

Highlights

The global spread of drug-resistant pathogens is a major threat to the control of infectious disease [1]
If artemisinin resistance, which recently appeared in Southeast Asia [4,5], continues to follow the same pattern, the world may soon find itself without reliable antimalarial drugs
We describe a study of naturally acquired P. falciparum infections in which we sought to determine whether within-host competition occurs in mixed-strain infections and whether drug-resistant parasites suffer competitive suppression

Summary

Introduction

The global spread of drug-resistant pathogens is a major threat to the control of infectious disease [1]. In the first analysis, which included the samples from all three countries, we used a linear mixed-effects model (using the function lmer in the R package lme4 [37]) to analyse the effects of infection type (single- versus mixed-genotype) and country (Angola, Ghana or Tanzania), as well as site within country (see electronic supplementary material, table S1, for study sites within each country).

Results

Conclusion