In high-transmission endemic regions, local populations of {\it Plasmodium falciparum} exhibit vast diversity of the \textit{var} genes encoding its major surface antigen, with each parasite comprising multiple copies from this diverse gene pool. This strategy to evade the immune system through large combinatorial antigenic diversity is common to other hyperdiverse pathogens. It underlies a series of fundamental epidemiological characteristics, including large reservoirs of transmission from high prevalence of asymptomatics and long-lasting infections. Previous theory has shown that negative frequency-dependent selection (NFDS) mediated by the acquisition of specific immunity by hosts structures the diversity of \textit{var} gene repertoires, or strains, in a pattern of limiting similarity that is both non-random and non-neutral. A combination of stochastic agent-based models and network analyses has enabled the development and testing of theory in these complex adaptive systems, where assembly of local parasite diversity occurs under frequency-dependent selection and large pools of variation. We show here the application of these approaches to theory comparing the response of the malaria transmission system to intervention when strain diversity is assembled under (competition-based) selection vs. a form of neutrality, where immunity depends only on the number but not the genetic identity of previous infections. The transmission system is considerably more persistent under NFDS, exhibiting a lower extinction probability despite comparable prevalence during intervention. We explain this pattern on the basis of the structure of strain diversity, in particular the more pronounced fraction of highly dissimilar parasites. For simulations that survive intervention, prevalence under specific immunity is lower than under neutrality, because the recovery of diversity is considerably slower than that of prevalence and decreased \textit{var} gene diversity reduces parasite transmission. A Principal Component Analysis of network features describing parasite similarity reveals that despite lower overall diversity, NFDS is quickly restored after intervention constraining strain structure and maintaining patterns of limiting similarity important to parasite persistence. Given the described enhanced persistence under perturbation, intervention efforts will likely require longer times than the usual practice to eliminate \textit{P. falciparum} populations. We discuss implications of our findings and potential analogies for ecological communities with non-neutral assembly processes involving frequency-dependence.

中文翻译：

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菌株之间的频率依赖性竞争使恶性疟原虫疟疾传播模型中的扰动持续存在

在高传播流行地区，恶性疟原虫的当地种群表现出编码其主要表面抗原的 \textit{var} 基因的巨大多样性，每个寄生虫都包含来自这个多样化基因库的多个拷贝。这种通过大的组合抗原多样性逃避免疫系统的策略对于其他超多样性病原体是常见的。它是一系列基本流行病学特征的基础，包括无症状高流行率和长期感染的大量传播库。先前的理论表明，由宿主获得特异性免疫介导的负频率依赖性选择（NFDS）以非随机和非随机的限制相似性的模式构建了\textit{var}基因库或菌株的多样性。非中性。基于随机代理的模型和网络分析的结合使这些复杂的自适应系统中的理论得以发展和测试，其中局部寄生虫多样性的组装发生在频率相关的选择和大量的变异池中。我们在这里展示了这些方法在理论中的应用，比较了在（基于竞争的）选择下组装菌株多样性与中性形式时疟疾传播系统对干预的反应，其中免疫仅取决于数量而不是遗传以前感染的身份。在 NFDS 下，传输系统的持久性要强得多，尽管干预期间的流行率相当，但它的灭绝概率较低。我们根据菌株多样性的结构来解释这种模式，特别是高度不同的寄生虫的更明显部分。对于在干预后存活的模拟，特异性免疫下的流行率低于中性下的流行率，因为多样性的恢复比流行率的恢复慢得多，并且 \textit{var} 基因多样性降低会减少寄生虫传播。描述寄生虫相似性的网络特征的主成分分析表明，尽管整体多样性较低，但在干预约束应变结构和保持对寄生虫持久性很重要的限制相似性模式后，NFDS 很快恢复。鉴于所描述的在扰动下增强的持久性，干预工作可能需要比通常做法更长的时间来消除 \textit{P. 恶性疟原虫}种群。