RAPID: Immune Responses to CoV Infections in African and North American Bats

RAPID：非洲和北美蝙蝠对冠状病毒感染的免疫反应

• 批准号: 2032774
• 负责人: Ken Field
• 金额: $ 20万
• 依托单位: Bucknell University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2032774&HistoricalAwards=false
• 关键词: RAPID; Immune; Responses; CoV; Infections

Bats appear to have co-evolved with coronaviruses (CoVs) for millennia. The CoVs that bats carry include the closest relatives of SARS-COV-2, the causative agent of COVID-19. The relationship between the bat host and CoV virus appears to have selected for immune tolerance that enables bats to control CoV replication and yet avoid immune damage. Although some novel CoV hosts (humans) are able to manage and clear the virus without significant consequence, many do not, falling victim instead to a pathological inflammatory response that results from overly-exuberant immune signaling. Understanding how bats avoid this deleterious path may provide insight into new disease mitigation strategies. The researchers supported by this award will leverage a large existing set of bat samples to better understand how bats respond to infection with CoVs. Beyond these direct COVID-19 societal benefits, this project will benefit society by training young scientists in disease ecology and in bioinformatics, preparing them for future careers in the transdisciplinary STEM workforce. Data from this study will be published in peer-reviewed journals, presented at scientific meetings, and shared through public data repositories.The purpose of this study is to identify immune mechanisms associated with tolerance of Coronavirus (CoV) infections in bats. Gaining information on bat responses to CoV infections will shed light on the mechanisms of effective immune control. Parallel study of (1) the CoV virome, and (2) the accompanying gene up- or down-regulation in response to infection will reveal immune system signatures of viral tolerance and advance fundamental understandings of antiviral immunity. By comparing responses in the African little epauletted fruit bat (Epomophorus labiatus), which host beta-CoVs, and the North American little brown myotis (Myotis lucifugus), which host alpha-CoVs, the common mechanisms of tolerance to both alpha- and beta-CoVs will be determined. A powerful dual RNA sequencing approach will be deployed to simultaneously sequence the virome and the host transcriptome. Using weighted gene correlation network analysis, gene expression counts will be used to determine gene networks in the host that are most tightly correlated to each CoV infection. These correlated gene networks will be analyzed functionally to determine which immune pathways are associated with CoV tolerance by either blocking inflammation and immune activation or by dampening tissue damage. Finally, the functions of these co-regulated genes will be compared to those documented in novel hosts (human and other animals). This RAPID award is made by the Physiological and Structural Systems Cluster in the BIO Division of Integrative Organismal Systems, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

蝙蝠似乎与冠状病毒（CoV）共同进化了数千年。蝙蝠携带的冠状病毒包括SARS-COV-2的近亲，SARS-COV-2是COVID-19的病原体。蝙蝠宿主和冠状病毒之间的关系似乎选择了免疫耐受，使蝙蝠能够控制冠状病毒复制，但避免免疫损伤。虽然一些新的CoV宿主（人类）能够管理和清除病毒而没有显著的后果，但许多人不能，而是成为过度旺盛的免疫信号导致的病理性炎症反应的受害者。了解蝙蝠如何避免这种有害的路径可能会提供新的疾病缓解策略的见解。该奖项支持的研究人员将利用大量现有的蝙蝠样本，以更好地了解蝙蝠如何应对冠状病毒感染。除了这些直接的COVID-19社会效益外，该项目还将通过培训疾病生态学和生物信息学方面的年轻科学家来造福社会，为他们未来在跨学科STEM劳动力中的职业生涯做好准备。 这项研究的数据将发表在同行评议的期刊上，在科学会议上发表，并通过公共数据库共享。这项研究的目的是确定与蝙蝠对冠状病毒（CoV）感染的耐受性相关的免疫机制。获得蝙蝠对CoV感染反应的信息将有助于阐明有效免疫控制的机制。对（1）CoV病毒组和（2）伴随基因在感染后的上调或下调的平行研究将揭示病毒耐受性的免疫系统特征，并推进抗病毒免疫的基本理解。通过比较非洲小肩果蝠（Epomophorus labiatus）（其宿主是β-CoV）和北美小棕鼠耳蝠（Myotis lucifugus）（其宿主是α-CoV）的反应，将确定对α-和β-CoV的耐受性的共同机制。一个强大的双RNA测序方法将被部署，同时测序病毒组和宿主转录组。使用加权基因相关网络分析，基因表达计数将用于确定宿主中与每个CoV感染最紧密相关的基因网络。这些相关的基因网络将进行功能分析，以确定哪些免疫途径与冠状病毒耐受性相关，通过阻断炎症和免疫激活或抑制组织损伤。最后，将这些共调节基因的功能与新宿主（人类和其他动物）中记录的功能进行比较。该RAPID奖项由BIO综合有机系统部门的生理和结构系统集群颁发，使用冠状病毒援助，救济和经济安全（CARES）法案的资金。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。