title: Within-host competition and drug resistance in the human malaria parasite Plasmodium falciparum.
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.
authors.affiliation: Department of Biology, Emory University, Atlanta, GA 30322, USA Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA mbushma@emory.edu.
authors.forename: Mary
authors.identifier: http://orcid.org/0000-0003-0933-5053
authors.initials: M
authors.lastname: Bushman
authors.affiliation: Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Morton
authors.affiliation: Epidemiology Department, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana.
authors.forename: Nancy
authors.identifier: http://orcid.org/0000-0001-8819-1793
authors.initials: N
authors.lastname: Duah
authors.affiliation: Epidemiology Department, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana Centre for Tropical Clinical Pharmacology and Therapeutics, University of Ghana Medical School, Accra, Ghana.
authors.forename: Neils
authors.initials: N
authors.lastname: Quashie
authors.affiliation: Epidemiology Department, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Abuaku
authors.affiliation: Epidemiology Department, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana.
authors.forename: Kwadwo A
authors.initials: KA
authors.lastname: Koram
authors.affiliation: National Malaria Control Program, Luanda, Angola.
authors.forename: Pedro Rafael
authors.initials: PR
authors.lastname: Dimbu
authors.affiliation: Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA Epidemic Intelligence Service, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Plucinski
authors.affiliation: Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Gutman
authors.affiliation: Ifakara Health Institute, Dar es Salaam, Tanzania.
authors.forename: Peter
authors.initials: P
authors.lastname: Lyaruu
authors.affiliation: Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: S Patrick
authors.initials: SP
authors.lastname: Kachur
authors.affiliation: Department of Biology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Jacobus C
authors.initials: JC
authors.lastname: de Roode
authors.affiliation: Malaria Branch, Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
authors.forename: Venkatachalam
authors.initials: V
authors.lastname: Udhayakumar
mesh_terms: D000810:Angola; D000962:Antimalarials / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D002738:Chloroquine / Q000494:pharmacology*; D004351:Drug Resistance; D005869:Ghana; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D013636:Tanzania
chemical_list: D000962:Antimalarials; D002738:Chloroquine
keywords: Plasmodium falciparum; chloroquine; competition; malaria; resistance; within-host