Understanding the Risk of Bat Coronavirus Emergence

了解蝙蝠冠状病毒出现的风险

• 批准号: 10216930
• 负责人: Peter Daszak
• 金额: $ 57.63万
• 依托单位: ECOHEALTH ALLIANCE, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10216930
• 关键词: 2019-nCoV; ACE2; Acute; Affinity; Amino Acid Sequence; Animals; Antibodies; Archives; Asia; Award; Behavior assessment; Binding; Biological; Biological Assay; COVID-19; COVID-19 outbreak; COVID-19 pandemic; Cell Culture Techniques; Cells; Characteristics; China; Chiroptera; Climate; Clinic; Communities; Complex; Computer Models; Coronavirus; Coronavirus Infections; Country; Data; Databases; Development; Diagnostic; Disease Outbreaks; First Independent Research Support and Transition Awards; Funding; Future; Genetic; Genetic Recombination; Genome; Genomic Segment; Goals; Human; In Vitro; Individual; Influenza; Laboratory Animal Models; Laboratory Animals; Maps; Measures; Middle East Respiratory Syndrome; Middle East Respiratory Syndrome Coronavirus; Modeling; Modification; Neutralization Tests; Patients; Pattern; Persons; Phylogenetic Analysis; Process; Protein Sequence Analysis; Proteins; Public Health; Publishing; Readiness; Reagent; Reporting; Research; Respiratory Disease; Risk; Risk Factors; SARS coronavirus; SARS-CoV-2 infection; SARS-CoV-2 variant; Sampling; Serology; Serum; Severe Acute Respiratory Syndrome; Singapore; Surveys; Technology; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Monoclonal Antibodies; United States National Institutes of Health; Vaccines; Viral; Viral Genome; Viral Proteins; Virus; Virus Diseases; Work; Zoonoses; biosecurity; coronavirus pandemic; epidemiologic data; evidence base; experimental study; exposure route; fighting; future pandemic; global health; high risk; human population study; in silico; novel; novel coronavirus; pandemic disease; prevent; programs; public health relevance; receptor; recombinant virus; respiratory; risk prediction; sample archive; seropositive; spillover event; syndromic surveillance; trait; vaccine development; vaccine evaluation; virus culture; virus host interaction; whole genome; zoonotic coronavirus

Modified Project Summary/Abstract Section Zoonotic coronaviruses (CoVs) are a significant threat to global health, as demonstrated by the emergence of SARS, MERS, and COVID-19. Our group identified bats as the wildlife reservoirs of SARS-CoV, and we have now published hundreds of novel SARS-related CoV (SARSr-CoV) sequences. Work under our previous NIH funding, and by others, has demonstrated that bats in Asia harbor an extraordinary diversity of SARSr-CoVs, some of which can use human ACE2 for cell entry, cause SARS-like illness in laboratory animals, and may evade current therapies or vaccines. Our analysis of ecological and human serological data indicates a median of around 66,000 people are infected by bat-SARSr-CoVs in the region each year, with unknown public health impacts. In this modification to our renewed R01, first awarded in 2019, we plan three aims: Aim 1. Analyze more than 300 full genomes/large genome segments of bat SARSr-CoVs from our prior bat sampling in southern China to identify viral characteristics, host biological traits, and environmental/ecological factors that lead to ‘recombination hotspots’. We will use host range modeling, complex phylogenetics, and ecological, environmental and demographic data to assess factors that may enhance recombination. We will also analyze spillover risk from over 200 other bat CoV RdRp sequences identified in our prior work to assess the generality of correlates of SARSr-CoV spillover risk for all bat-CoVs; Aim 2. Use our community- and clinic-based survey data and archived pre-COVID-19 human samples to identify putative SARSr-CoV spillover events, routes of exposure, and potential public health consequences. We will test samples with a SARSr-CoV ACE2 surrogate virus neutralization to identify pre-COVID-19 infection with SARSr-CoVs and other ACE2 binding CoVs. We will test archived clinic-based syndromic surveillance samples to assess if patients presenting with influenza-like illness and severe acute respiratory illness have PCR or serological evidence of SARSr-CoV infection; Aim 3. Use computer modeling and cell culture to analyze potential binding interactions among novel bat-CoVs, putative reservoir and intermediate hosts, and people, to validate spillover predictions from Aims 1 & 2. Rather than use recombinant virus technology, we will estimate CoV binding to human cells using amino acid sequence analysis, modeling of RBD binding to human, bat & other putative host ACE2 and other receptors, and binding assays with non-infectious viral proteins and pseudovirus technology in vitro. We will then test our hypothesis that SARSr-CoVs with 10-25% spike protein sequence divergence from SARS-CoV or SARS-CoV-2 are able to infect human cells, and evade therapeutics and vaccines. Work from all three aims will help demonstrate proof-of-concept that our bat CoV program is a model platform to integrate analysis of virological and ecological factors contributing to CoV emergence and inform high impact strategies to prevent future pandemics. This includes providing critical reagents, therapeutic interventions, and viral genome sequences for pandemic and public health preparedness to counter future potential coronavirus outbreaks.

修改后的项目摘要/摘要部分 人畜共患冠状病毒 (CoV) 对全球健康构成重大威胁，SARS、MERS 和 COVID-19 的出现就证明了这一点。我们的研究小组确定蝙蝠是 SARS-CoV 的野生动物宿主，目前我们已经发布了数百种新型 SARS 病毒。相关的 CoV (SARSr-CoV) 序列。我们之前的 NIH 资助和其他人的研究表明，亚洲的蝙蝠具有非凡的 SARSr-CoV 多样性，其中一些可以利用人类 ACE2 进入细胞，在实验动物中引起类似 SARS 的疾病，并且可能逃避当前的治疗或疫苗。我们对生态和人类血清学数据的分析表明，该地区每年约有 66,000 人感染蝙蝠 SARSr-CoV，而公共卫生状况未知。在对 2019 年首次授予的 R01 的修改中，我们计划实现三个目标： 目标 1. 分析蝙蝠 SARSr-CoV 的 300 多个完整基因组/大基因组片段。根据我们之前在中国南方进行的蝙蝠采样，以确定导致“重组热点”的病毒特征、宿主生物特征和环境/生态因素，我们将使用宿主范围模型、复杂的系统发育以及生态、环境和人口数据来评估因素。我们还将分析我们之前工作中发现的 200 多个其他蝙蝠 CoV RdRp 序列的溢出风险，以评估所有蝙蝠 冠状病毒 SARSr 冠状病毒溢出风险相关性的普遍性；目标 2. 使用我们基于社区和诊所的调查数据和存档的 COVID-19 之前的人类样本来确定假定的 SARSr-CoV 溢出事件、暴露途径和潜在的公共卫生后果。我们将使用 SARSr-CoV 测试样本。 ACE2 替代病毒中和，以识别 SARSr-CoV 和其他 ACE2 结合 CoV 的 COVID-19 前感染。我们将测试存档的临床综合征监测样本，以评估患者是否出现流感样症状。目标 3：使用计算机建模和细胞培养来分析新型蝙蝠冠状病毒、假定储存宿主和中间宿主以及人之间的潜在结合相互作用，以验证溢出预测来自目标 1 和 2。我们将不使用重组病毒技术，而是使用氨基酸序列分析、RBD 与人类、蝙蝠和其他假定宿主 ACE2 及其他受体结合的建模来估计 CoV 与人类细胞的结合，以及然后，我们将使用非感染性病毒蛋白和假病毒技术进行体外结合试验，验证我们的假设，即与 SARS-CoV 或 SARS-CoV-2 具有 10-25% 刺突蛋白序列差异的 SARSr-CoV 能够感染人类细胞。所有三个目标的工作将有助于证明我们的蝙蝠冠状病毒计划是一个模型平台，可以整合对导致冠状病毒出现的病毒学和生态因素的分析，并为高影响策略提供信息预防未来的大流行。这包括为大流行和公共卫生做好准备提供关键试剂、治疗干预措施和病毒基因组序列，以应对未来潜在的冠状病毒爆发。

项目成果

Serological Evidence of Bat SARS-Related Coronavirus Infection in Humans, China.

中国人类蝙蝠 SARS 相关冠状病毒感染的血清学证据。

• 发表时间: 2018-02
• 影响因子: 5.5
• 作者: Wang, Ning;Li, Shi;Yang, Xing;Huang, Hui;Zhang, Yu;Guo, Hua;Luo, Chu;Miller, Maureen;Zhu, Guangjian;Chmura, Aleksei A;Hagan, Emily;Zhou, Ji;Zhang, Yun;Wang, Lin;Daszak, Peter;Shi, Zheng
• 通讯作者: Shi, Zheng

Comparative analysis of rodent and small mammal viromes to better understand the wildlife origin of emerging infectious diseases.

比较分析啮齿动物和小型哺乳动物病毒组，以更好地了解新发传染病的野生动物起源。

• 发表时间: 2018-10-03
• 影响因子: 15.5
• 作者: Wu, Zhiqiang;Lu, Liang;Du, Jiang;Yang, Li;Ren, Xianwen;Liu, Bo;Jiang, Jinyong;Yang, Jian;Dong, Jie;Sun, Lilian;Zhu, Yafang;Li, Yuhui;Zheng, Dandan;Zhang, Chi;Su, Haoxiang;Zheng, Yuting;Zhou, Hongning;Zhu, Guangjian;Li, Hongying;Chmura
• 通讯作者: Chmura

Opinion: Sustainable development must account for pandemic risk.

观点：可持续发展必须考虑到流行病风险。

• 发表时间: 2020-02-25
• 影响因子: 11.1
• 作者: Di Marco, Moreno;Baker, Michelle L;Daszak, Peter;De Barro, Paul;Eskew, Evan A;Godde, Cecile M;Harwood, Tom D;Herrero, Mario;Hoskins, Andrew J;Johnson, Erica;Karesh, William B;Machalaba, Catherine;Garcia, Javier Navarro;Paini, Dean;Pirzl, Reb
• 通讯作者: Pirzl, Reb

Extreme mobility of the world's largest flying mammals creates key challenges for management and conservation.

世界上最大的飞行哺乳动物的极端流动性给管理和保护带来了重大挑战。

• 发表时间: 2020-08-21
• 影响因子: 5.4
• 作者: Welbergen, Justin A;Meade, Jessica;Field, Hume E;Edson, Daniel;McMichael, Lee;Shoo, Luke P;Praszczalek, Jenny;Smith, Craig;Martin, John M
• 通讯作者: Martin, John M

Isolation and Characterization of a Novel Bat Coronavirus Closely Related to the Direct Progenitor of Severe Acute Respiratory Syndrome Coronavirus.

与严重急性呼吸系统综合症冠状病毒直接祖细胞密切相关的新型蝙蝠冠状病毒的分离和表征。

• 发表时间: 2015-12-30
• 作者: Yang, Xing;Hu, Ben;Wang, Bo;Wang, Mei;Zhang, Qian;Zhang, Wei;Wu, Li;Ge, Xing;Zhang, Yun;Daszak, Peter;Wang, Lin;Shi, Zheng
• 通讯作者: Shi, Zheng