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

研究总结 最近寨卡病毒(ZIKV)进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)和蚊子中进入一个演绎周期。病原体的能力 能否成为新的寄主物种，在一定程度上取决于该病原体在新物种中的毒力。 目前关于毒力进化的理论建立在病原菌适应性最大化的前提下 优化瞬时病原体传播率和感染持续时间之间的权衡。虽然大多数人 毒力进化的理论研究主要集中在传播和寄主之间的权衡。 死亡，大多数病原体不会杀死它们的宿主。相反，大多数感染是由宿主减少的 免疫反应，导致传播和清除之间的权衡。变速器间隙的研究 权衡是很少的，但我们之前发现，在文献中的多项研究中，存在一个 节肢动物传播病毒时，病毒滴度峰值与感染持续时间成反比 通过实验接种到自然宿主中。此外，我们还利用这些数据对备选方案进行建模 传播策略，即低强度、长时间病毒血症的“乌龟”策略和“野兔”策略 短时间、高强度病毒血症的策略，并发现采用乌龟策略的虫媒病毒 在宿主和媒介种群中都有较高的持续率。尽管如此，目前对 虫媒病毒的传播-清除权衡是基本的，并且是集成的实验和模型 需要对生态相关宿主和媒介物种中的虫媒病毒进行权衡研究，以适当地 评估在新地区建立海尔干旋回的风险以及随后出现的风险 这样的循环。为此，我们将量化ZIKV和登革病毒(DENV)感染的动态，免疫 在原生NHP宿主(食蟹猴)以及新的美国NHP中的反应和传播 (松鼠猴子)识别变速器-净空之间的权衡，我们将建立模型来预测影响 在宿主群体中病毒持久性的这种权衡。DENV被选为ZIKV的对应物 因为，尽管它在美洲的人类中传播了几个世纪，但它还没有建立起一个美国人 森林循环[17]。我们将检验四个具体的假设：(I)在本地寄主和新寄主中， 虫媒病毒经历了传播清除的权衡；(Ii)在本地和新宿主中，先天免疫 反应决定了传播-清除的权衡；(Iii)树突状虫媒病毒经历不同 原生寄主和新寄主的传播清除权衡，导致来自新寄主的传播量较少 宿主；(4)来自人-地方性传播周期的DENV和ZIKV谱系经历不同的 在原生NHP宿主中的传播-清除权衡，但相似的模式 新奇的NHP主持人。

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.