Within-host competition can delay evolution of drug resistance in malaria

• Type of Material: Article
• Authors: Mary Bushman, Emory University; Rustom Antia, Emory University; Venkatachalam Udhayakumar, Centers for Disease Control and Prevention; Jacobus De Roode, Emory University
• Language: English
• Date: 2018-08-21
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
• License: Creative Commons Creative Commons CC0 1.0 Universal
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pbio.2005712
• Title of Journal or Parent Work: PLoS Biology
• ISSN: 1544-9173
• Volume: 16
• Issue: 8
• Start Page: e2005712
• End Page: e2005712
• Grant/Funding Information: This work was partially funded from Emory University’s Open Access Publishing Fund.; Centers for Disease Control and Prevention Antimicrobial Resistance Working Group, Atlanta Research and Education Foundation (grant number KMR1B7), and Emory University.

Abstract

In the malaria parasite P. falciparum, drug resistance generally evolves first in low-transmission settings, such as Southeast Asia and South America. Resistance takes noticeably longer to appear in the high-transmission settings of sub-Saharan Africa, although it may spread rapidly thereafter. Here, we test the hypothesis that competitive suppression of drug-resistant parasites by drug-sensitive parasites may inhibit evolution of resistance in high-transmission settings, where mixed-strain infections are common. We employ a cross-scale model, which simulates within-host (infection) dynamics and between-host (transmission) dynamics of sensitive and resistant parasites for a population of humans and mosquitoes. Using this model, we examine the effects of transmission intensity, selection pressure, fitness costs of resistance, and cross-reactivity between strains on the establishment and spread of resistant parasites. We find that resistant parasites, introduced into the population at a low frequency, are more likely to go extinct in high-transmission settings, where drug-sensitive competitors and high levels of acquired immunity reduce the absolute fitness of the resistant parasites. Under strong selection from antimalarial drug use, however, resistance spreads faster in high-transmission settings than low-transmission ones. These contrasting results highlight the distinction between establishment and spread of resistance and suggest that the former but not the latter may be inhibited in high-transmission settings. Our results suggest that within-host competition is a key factor shaping the evolution of drug resistance in P. falciparum.