Crossing scales to predict and prevent bat virus zoonoses in a Madagascar ecosystem

新冠肺炎大流行的广泛影响突显了跨物种的极端威胁 人畜共患病病原体的出现。蝙蝠(目：翼手目)是大多数蝙蝠的天然宿主 世界上最致命的人畜共患病病毒，包括亨德拉和尼帕埃尼帕病毒，埃博拉和马尔堡病毒 丝状病毒，以及SARS、MERS，现在是SARS-CoV-2冠状病毒。值得注意的是，蝙蝠几乎没有表现出 感染病毒可导致其他哺乳动物极端病理的疾病，可能在 部分原因是它们独特的抗炎分子适应，被认为是进化来缓解 在飞行过程中积累的生理损伤。令人惊讶的是，与世隔绝的岛屿蝙蝠群落 在世界各地支持多种病毒在临界以下人群中的地方性传播 相关病原体在其他宿主中持续存在所需的群落大小。自跨物种溢出以来 几种蝙蝠传播的病毒具有明显的季节性特征，与繁殖和繁殖的时间相吻合 对于有问题的蝙蝠宿主的营养压力，解开了控制传播的机制， 这些病毒在野生蝙蝠种群中的传播和持续存在对公共卫生具有至关重要的意义。部分地 随着这里提出的研究倡议，我们将使用分子和血清学工具来开发一种 流行性乙型流感病毒和冠状病毒免疫学和感染数据的纵向时间序列 马达加斯加的野生果蝠，利用我们长期野生动物监测工作中收集的样本。蝙蝠是 在马达加斯加被广泛消费作为人类食物来源，以及我们研究小组的初步数据 展示了全岛以前人类接触这些人畜共患病病毒的血清学特征。我们 建议将不同的动力学模型与所产生的人口水平数据相匹配，以便区分 在这些蝙蝠宿主中，支持季节性病毒脱落脉冲和伴随传播的机制。在……里面 除了种群水平的研究，我们还将在一只蝙蝠体内构建病毒控制的宿主模型 免疫系统，我们将与贝塔冠状病毒挑战的蝙蝠的实验感染数据相匹配 实验室，目的是破译促使病毒脱落的机制。我们的项目旨在 同时开发BAT细胞系和病毒的分子工具，以支持宿主内的研究 我们自己的马达加斯加系统。最后，我们将在人口水平和宿主内部研究的基础上，建立模型和 实施疫苗干预措施，旨在根除测试人群中正在传播的埃尼帕病毒 马达加斯加果蝠。广泛地说，我们的项目旨在使用场、分子、 以及建模工具，以在BAT病毒溢出事件发生之前对其进行预测和预防。

The wide-reaching impacts of the COVID-19 pandemic highlight the extreme threat posed by the cross-species emergence of zoonotic pathogens. Bats (order: Chiroptera) are the natural reservoir hosts for the majority of the world’s most virulent zoonotic viruses, including Hendra and Nipah henipaviruses, Ebola and Marburg filoviruses, and SARS, MERS, and now SARS-CoV-2 coronaviruses. Remarkably, bats exhibit little demonstrable disease upon infection with viruses that cause extreme pathology in other mammals, likely in part due to their unique anti-inflammatory molecular adaptations, which are thought to have evolved to mitigate the accumulation of physiological damage accrued during flight. Surprisingly, isolated island bat communities around the world support the endemic circulation of numerous viruses in populations below the critical community size required for persistence of related pathogens in other hosts. Since cross-species spillover of several bat-borne viruses bears a distinctive seasonal signature, coincident with the timing of reproductive and nutritional stress for the bat hosts in question, disentangling the mechanisms governing the transmission, circulation, and persistence of these viruses in wild bat populations is of critical public health interest. In part with the research initiatives proposed here, we will use molecular and serological tools to develop a longitudinal time series of immunological and infection data for henipaviruses and coronaviruses circulating in wild fruit bats in Madagascar, leveraging samples collected in our longterm wildlife surveillance effort. Bats are widely consumed as a source of human food in Madagascar, and preliminary data from our research group demonstrates serological signatures of prior human exposure to these zoonotic viruses across the island. We propose to fit disparate dynamical models to the resulting population-level data in order to distinguish mechanisms underpinning seasonal viral shedding pulses and concomitant transmission in these bat hosts. In addition to population-level studies, we will also construct within-host models of viral control in a single bat immune system, which we will fit to experimental infection data from Betacoronavirus-challenged bats in the laboratory, with the aim of deciphering the mechanisms which motivate viral shedding. Our project aims to simultaneously develop molecular tools of bat cell lines and viruses with which to support within-host studies in our own Madagascar system. Finally, we will build on population-level and within-host studies to model and implement a vaccine intervention designed to eradicate circulating henipavirus from a test-population of Madagascar fruit bats. Broadly, our project aims to use a uniquely integrative combination of field, molecular, and modeling tools to enable the prediction and prevention of bat virus spillover events before they occur.