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

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") and within-host competition both 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 common, resistant lineages. In contrast, in low transmission populations, we observed that common, 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 in the population. Once resistance was common enough to be found on many antigenic backgrounds, immune selection stably maintained resistance in the population because resistance was able to proliferate, even in untreated hosts, when it was linked to a novel epitope. The results of our simulations demonstrate that immune selection plays a major role in observed dynamics of resistance evolution. Author summaryDrug resistance in the malaria parasite, Plasmodium falciparum, presents an ongoing public health challenge, but aspects of its evolution are poorly understood. Although antimalarial resistance is common worldwide, it can typically be traced to just a handful of origins. Counterintuitively, although Sub Saharan Africa bears 90% of the global malaria burden, resistance typically originates in regions where transmission intensity is low. In high transmission regions, infections are genetically diverse, and hosts have significant standing adaptive immunity, both of which are known to suppress frequency of resistance within infections. However, interactions between immune-driven selection, transmission intensity, and resistance have not been investigated. Using a multiscale, agent-based model, we found that high transmission intensity slowed the evolution of resistance in two ways. First, it intensified competition, allowing sensitive lineages to suppress resistant lineages. Second, high population immunity selected for antigenic novelty, which interfered with selection for resistance. However, once resistance was at a high frequency, immune selection maintained it in the population at a high prevalence. Our findings provide a novel explanation for observations about the origin of resistance and demonstrate that adaptive immunity is a critical component of selection.