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.

The effect of drug dose and timing of treatment on the emergence of drug resistancein vivoin a malaria model

“…In the limit, this is clearly true, but if concentrations sufficient to kill all resistant mutants cannot be achieved, populations of surviving mutants rapidly expand to fill the niche vacated when pathogens are killed by chemotherapy [3,4,[23][24][25]. This process of niche expansion (also called 'competitive release') has been demonstrated in animal disease models [24,[26][27][28] and in humans [29,30]. Competitive release means that in the simplest case, the relationship between drug dose and resistance emergence is an 'inverted U': at very low doses, there is no selection for resistance, at high doses, everything is killed, and in between, resistance evolution is promoted [3,4,31] .…”

Within-infection diversity ofPlasmodium falciparumantigens reflects host-mediated selection

“…The utility of this approach, however, extends beyond questions of immune selection. There is growing recognition that intra-host dynamics must be considered when studying diverse aspects of Plasmodium biology, including drug resistance [52,53], disease severity [54][55][56][57], and transmission rate [58,59]. Our observations show that human-mediated selection on P. falciparum is sufficiently strong to be detected using measures of within-infection diversity and demonstrate the utility of incorporating evolutionary approaches into Plasmodium studies.…”

South-East Asian strains of Plasmodium falciparum display higher ratio of non-synonymous to synonymous polymorphisms compared to African strains

“…Mixed strain infection by P. falciparum has recently been demonstrated to lead to within-host competition in patients 22 , the possible mechanisms of which might include strain-transcending immunity, resource competition (e.g. RBCs) or direct interference between strains 23– 26 .…”