Trade-offs between Arbovirus Transmission and Clearance in Native and Novel Hosts

研究综述 最近寨卡病毒（ZIKV）传入新大陆引发了人们对该病毒将出现的担忧 在美国非人类灵长类动物（NHP）和蚊子中进入森林化周期。病原体能够 出现在新的宿主物种中的时间部分地由该病原体在新物种中的毒力决定。 目前关于毒力进化的理论基于以下前提： 优化瞬时病原体传播性和感染持续时间之间的权衡。虽然大多数 毒力进化的理论研究集中在传播和宿主之间的权衡 死亡率，大多数病原体不会杀死它们的宿主。相反，大多数感染被宿主抑制 免疫反应，导致传播-清除权衡。传输间隙的研究 权衡是罕见的，但我们以前发现，在文献中的多项研究中， 当节肢动物传播病毒被感染时， 实验性地接种到自然宿主中。此外，我们利用这些数据来模拟替代方案， 传播策略，即低强度、长时间病毒血症的“乌龟”策略和“兔子”策略， 短持续时间，高幅度病毒血症的策略，并发现采取乌龟策略的虫媒病毒 在宿主和病媒种群中的持久性较高。然而，目前对 虫媒病毒的传播-清除权衡是基本的，综合实验和建模 需要对虫媒病毒在生态相关宿主和媒介物种中的权衡进行研究， 评估在新地区建立森林循环的风险以及随后出现森林循环的风险。 这样的循环。为此，我们将量化ZIKV和登革病毒（DENV）感染、免疫应答和免疫应答的动态。 本土NHP宿主（食蟹猴）以及新型美国NHP的反应和传播 （松鼠猴）来确定传输-清除的权衡，我们将建立模型来预测影响 病毒在宿主种群中的持久性。选择DENV作为ZIKV的对应物 因为，尽管它在美洲的人类中传播了几个世纪，但它还没有在美国建立一个 森林循环[17]。我们将测试四个具体的假设：（i）在天然宿主和新宿主中， 虫媒病毒的经验，传播清除权衡;（ii）在天然和新的主机，先天免疫 响应形状的传输清除权衡;（三）森林虫媒病毒的经验不同 在原生宿主和新型宿主中的传播-清除权衡，导致来自新型宿主的传播较少 （iv）来自人类地方性传播周期的DENV和ZIKV谱系经历不同的感染; 在天然NHP宿主中，它们的森林祖先比它们的森林祖先具有更高的传输清除权衡，但在 新型NHP宿主。

Research Summary The recent introduction of Zika virus (ZIKV) into the New World sparked concern that the virus would emerge into a sylvatic cycle in American non-human primates (NHPs) and mosquitoes. The ability of a pathogen to emerge into a novel host species is determined, in part, by the virulence of that pathogen in the novel species. Current theory on the evolution of virulence rests on the premise that pathogen fitness is maximized by optimizing the trade-off between instantaneous pathogen transmissibility and duration of infection. While most theoretical studies of virulence evolution have focused on the trade-off between transmission and host mortality, the majority of pathogens do not kill their hosts. Instead, most infections are curtailed by the host immune response, leading to a transmission-clearance trade-off. Studies of the transmission-clearance trade-off are scarce, but we have previously found that, across multiple studies in the literature, there is an inverse relationship between peak virus titer and duration of infection when arthropod-borne viruses are experimentally inoculated into natural hosts. Moreover, we have leveraged these data to model alternate transmission strategies, namely a “tortoise” strategy of low magnitude, long duration viremia and a “hare” strategy of short duration, high magnitude viremia and found that arboviruses that adopted a tortoise strategy had higher rates of persistence in both host and vector populations. Nonetheless current understanding of transmission-clearance trade-offs in arboviruses is rudimentary, and integrated experimental and modeling studies of arbovirus trade-offs in ecologically-relevant host and vector species are needed to appropriately assess the risk of establishment of sylvatic cycles in new areas and the subsequent risk of emergence from such cycles. To this end, we will quantify dynamics of ZIKV and dengue virus (DENV) infection, immune response, and transmission in native NHP hosts (cynomolgus macaques) as well as novel, American NHPs (squirrel monkeys) to identify transmission-clearance trade-offs, and we will build models to predict the impact of such trade-offs on virus persistence in host populations. DENV is chosen as a counterpoint to ZIKV because, despite circulating in humans in the Americas for centuries, it has not yet established an American sylvatic cycle [17]. We will test four specific hypotheses: (i) In native hosts and novel hosts, sylvatic arboviruses experience a transmission-clearance trade-off; (ii) In native and novel hosts, the innate immune response shapes the transmission-clearance trade-off; (iii) Sylvatic arboviruses experience different transmission-clearance trade-offs in native hosts and novel hosts, resulting in less transmission from novel hosts; (iv) DENV and ZIKV lineages from human-endemic transmission cycles experience different transmission-clearance trade-offs than their sylvatic ancestors in native NHP hosts, but similar patterns in novel NHP hosts.