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

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COVID-19病原体SARS-COV-2的近亲。蝙蝠宿主与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的复制，同时避免免疫损伤。尽管一些新型冠状病毒宿主（人类）能够控制和清除病毒而不会产生重大后果，但许多宿主却不能，而是成为过度活跃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途径可能会为新的疾病缓解策略提供见解。该奖项支持的研究人员将利用现有的大量蝙蝠样本，更好地了解蝙蝠对冠状病毒感染的反应。除了这些COVID-19的直接社会效益外，该项目还将通过培训年轻科学家在疾病生态学和生物信息学方面的知识，为他们未来在跨学科STEM劳动力队伍中的职业生涯做好准备，从而造福社会。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。本研究的目的是确定与蝙蝠对冠状病毒感染耐受相关的免疫机制。获得蝙蝠对冠状病毒感染反应的信息将有助于阐明有效免疫控制的机制。平行研究(1)冠状病毒组和(2)伴随的基因在感染反应中上调或下调，将揭示病毒耐受的免疫系统特征，并推进对抗病毒免疫的基本理解。通过比较宿主为β -冠状病毒的非洲小肩胛果蝠（Epomophorus labiatus）和宿主为α -冠状病毒的北美小褐肌蝠（myotis lucifugus）的反应，将确定对α -冠状病毒和β -冠状病毒耐受的共同机制。一种强大的双RNA测序方法将被部署来同时测序病毒组和宿主转录组。利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种冠状病毒感染最密切相关的基因网络。将对这些相关基因网络进行功能分析，以确定哪些免疫途径通过阻断炎症和免疫激活或抑制组织损伤与冠状病毒耐受性相关。最后，将这些共调控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奖由综合有机体系统生物学部的生理和结构系统集群获得，资金来自《冠状病毒援助、救济和经济安全（CARES）法案》。该奖项反映了美国国家科学基金会的法定使命，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。

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.