Immune selection suppresses the emergence of drug resistance in malaria parasites but facilitates its spread.

Alexander O B Whitlock,Nicole Mideo,Jonathan J Juliano,Rustom Antia

doi:10.1371/journal.pcbi.1008577

Alexander O B Whitlock, Nicole Mideo + Show 2 more

Open Access

https://doi.org/10.1371/journal.pcbi.1008577

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Abstract

Although drug resistance in Plasmodium falciparum typically evolves in regions of low transmission, resistance spreads readily following introduction to regions with a heavier disease burden. This suggests that the origin and the spread of resistance are governed by different processes, and that high transmission intensity specifically impedes the origin. Factors associated with high transmission, such as highly immune hosts and competition within genetically diverse infections, are associated with suppression of resistant lineages within hosts. However, interactions between these factors have rarely been investigated and the specific relationship between adaptive immunity and selection for resistance has not been explored. Here, we developed a multiscale, agent-based model of Plasmodium parasites, hosts, and vectors to examine how host and parasite dynamics shape the evolution of resistance in populations with different transmission intensities. We found that selection for antigenic novelty (“immune selection”) suppressed the evolution of resistance in high transmission settings. We show that high levels of population immunity increased the strength of immune selection relative to selection for resistance. As a result, immune selection delayed the evolution of resistance in high transmission populations by allowing novel, sensitive lineages to remain in circulation at the expense of the spread of a resistant lineage.In contrast, in low transmission settings, we observed that resistant strains were able to sweep to high population prevalence without interference. Additionally, we found that the relationship between immune selection and resistance changed when resistance was widespread. Once resistance was common enough to be found on many antigenic backgrounds, immune selection stably maintained resistant parasites in the population by allowing them to proliferate, even in untreated hosts, when resistance was linked to a novel epitope. Our results suggest that immune selection plays a role in the global pattern of resistance evolution.

Highlights

Widespread drug resistance in Plasmodium falciparum malaria has been an ongoing public health challenge for decades, several observations about the evolution of resistance seem counterintuitive
Agent-based model, we found that high transmission intensity slowed the evolution of resistance via its effect on host population immunity
Once resistance was common in the circulating parasite population, immune selection maintained it in the population at a high prevalence

Summary

Introduction

Widespread drug resistance in Plasmodium falciparum malaria has been an ongoing public health challenge for decades, several observations about the evolution of resistance seem counterintuitive. Resistant lineages typically originate in regions with relatively low transmission intensity, such as South America or Southeast Asia. Once introduced to Africa, these resistant lineages spread readily. Resistance to chloroquine originated five times in South America and Southeast Asia [10] but only appeared in Africa once introduced from Asia [8] in 1978. Chloroquine resistance had been detected in every country in tropical Africa [11]. Together, these observations suggest that there is a dynamic that suppresses the spread of a resistance mutation immediately after its origin and, further, that this dynamic is intensified in high transmission settings. With millions of lives at stake, fully understanding the evolution of resistance is urgent

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