Department of Ecology & Evolutionary Biology, University of Toronto, Toronto, Canada.
Division of Infectious Diseases, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.
PLoS Comput Biol. 2021 Jul 19;17(7):e1008577. doi: 10.1371/journal.pcbi.1008577. eCollection 2021 Jul.
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.
尽管疟原虫对药物的耐药性通常在低传播地区进化，但在引入疾病负担较重的地区后，耐药性很容易传播。这表明耐药性的起源和传播受到不同过程的控制，高强度的传播特别阻碍了耐药性的起源。与高强度传播相关的因素，如高度免疫宿主和基因多样感染中的竞争，与宿主内耐药系的抑制有关。然而，这些因素之间的相互作用很少被研究，适应性免疫与耐药性选择之间的具体关系也没有被探索。在这里，我们开发了一个多尺度的、基于主体的疟原虫、宿主和媒介的模型，以研究宿主和寄生虫动力学如何在不同传播强度的种群中塑造耐药性的进化。我们发现，抗原新颖性的选择（“免疫选择”）抑制了高传播环境中的耐药性进化。我们表明，高水平的群体免疫增加了相对于耐药性选择的免疫选择强度。因此，免疫选择通过允许新的、敏感的谱系在传播中保持循环，而不是传播耐药谱系，从而延迟了高传播种群中耐药性的进化。相比之下，在低传播环境中，我们观察到耐药株能够在没有干扰的情况下横扫高人群流行率。此外，我们发现，当耐药性广泛存在时，免疫选择与耐药性之间的关系发生了变化。一旦耐药性在许多抗原背景上普遍存在，免疫选择通过允许它们在没有治疗的情况下繁殖，即使在与新表位相关的情况下，也能稳定地将耐药寄生虫维持在人群中。我们的研究结果表明，免疫选择在全球耐药性进化模式中发挥作用。
