Understanding the Risk of Bat Coronavirus Emergence

描述(申请人提供)：该项目将通过在中国的人-野生动物界面进行深入的实地调查，对新的冠状病毒和宿主受体结合域基因进行分子表征，传播和进化的数学模型，以及宿主范围的体外和体内实验室研究，来研究未来从野生动物中出现冠状病毒的风险。人畜共患病冠状病毒是对全球健康的重大威胁，2002年中国出现大流行严重急性呼吸综合征冠状病毒(SARS-CoV)，以及最近和正在出现的中东呼吸综合征(MERS-CoV)就证明了这一点。蝙蝠似乎是这些病毒的天然宿主，在过去的二十年里，已经发现了数百种新的蝙蝠冠状病毒。蝙蝠和其他野生动物物种在亚洲各地被猎杀、交易、屠宰和消费，形成了大规模的人与野生动物界面，未来出现新型CoV的风险很高。该项目旨在通过研究关键的人畜共患病宿主(BAT)、新兴疾病热点(中国)中新出现的高风险地点(野生动物市场)中的CoV多样性，来了解哪些因素会增加下一次出现CoV在人中的风险。本项目的三个具体目标是：1.评估中国地区高危人-野生动物交界处的冠状病毒溢出潜力。这将包括量化人们与蝙蝠和其他野生动物接触的性质和频率；对在湿货市场工作并高度接触野生动物的人进行血清学和分子筛查；使用分子分析从30多个物种中筛选野生捕获和市场采样的蝙蝠的冠状病毒；以及新型冠状病毒的基因组特征和分离。2.建立了蝙蝠冠状病毒发生风险和寄主范围的预测模型。一种组合的建模方法将包括宿主受体和新的冠状病毒基因(包括功能受体结合域)的系统发育分析；预测宿主范围和病毒共享的融合生态和进化模型；以及检验进化和传播动力学的数学矩阵模型。3.冠状病毒种间传播的检验预测。将使用反向遗传学、伪病毒和受体结合分析以及来自不同物种和人源化小鼠的一系列细胞培养的病毒感染实验，对宿主范围(即出现潜力)的预测模型进行实验测试。

DESCRIPTION (provided by applicant): This project will examine the risk of future coronavirus (CoV) emergence from wildlife using in-depth field investigations across the human-wildlife interface in China, molecular characterization of novel CoVs and host receptor binding domain genes, mathematical models of transmission and evolution, and in vitro and in vivo laboratory studies of host range. Zoonotic CoVs are a significant threat to global health, as demonstrated with the emergence of pandemic severe acute respiratory syndrome coronavirus (SARS-CoV) in China in 2002, and the recent and ongoing emergence of Middle East Respiratory Syndrome (MERS-CoV). Bats appear to be the natural reservoir of these viruses, and hundreds of novel bat-CoVs have been discovered in the last two decades. Bats, and other wildlife species, are hunted, traded, butchered and consumed across Asia, creating a large scale human-wildlife interface, and high risk of future emergence of novel CoVs. This project aims to understand what factors increase the risk of the next CoV emerging in people by studying CoV diversity in a critical zoonotic reservoir (bats), at sites of high risk for emergence (wildlife markets) in an emerging disease hotspot (China). The three specific aims of this project are to: 1. Assess CoV spillover potential at high risk human-wildlife interfaces in China. This will include quantifying he nature and frequency of contact people have with bats and other wildlife; serological and molecular screening of people working in wet markets and highly exposed to wildlife; screening wild-caught and market sampled bats from 30+ species for CoVs using molecular assays; and genomic characterization and isolation of novel CoVs. 2. Develop predictive models of bat CoV emergence risk and host range. A combined modeling approach will include phylogenetic analyses of host receptors and novel CoV genes (including functional receptor binding domains); a fused ecological and evolutionary model to predict host-range and viral sharing; and mathematical matrix models to examine evolutionary and transmission dynamics. 3. Test predictions of CoV inter-species transmission. Predictive models of host range (i.e. emergence potential) will be tested experimentally using reverse genetics, pseudovirus and receptor binding assays, and virus infection experiments across a range of cell cultures from different species and humanized mice.