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新冠肺炎的病原体SARS-COV-2的近亲。蝙蝠宿主和冠状病毒病毒之间的关系似乎是出于免疫耐受性的选择，使蝙蝠能够控制冠状病毒复制，同时避免免疫损害。虽然一些新的冠状病毒宿主(人类)能够在不造成重大后果的情况下管理和清除病毒，但许多人没有，而是成为由过度活跃的免疫信号引起的病理性炎症反应的受害者。了解蝙蝠如何避免这条有害的路径，可能会为新的疾病缓解策略提供洞察。该奖项支持的研究人员将利用现有的大量蝙蝠样本来更好地了解蝙蝠对冠状病毒感染的反应。除了新冠肺炎的这些直接社会效益，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的STEM劳动力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。这项研究的目的是确定与蝙蝠对冠状病毒(CoV)感染的耐受性有关的免疫机制。获得有关蝙蝠对冠状病毒感染的反应的信息将有助于阐明有效的免疫控制机制。对(1)冠状病毒病毒体和(2)伴随基因在感染后上调或下调的平行研究将揭示病毒耐受的免疫系统特征，并促进对抗病毒免疫的基本理解。通过比较寄主甲型冠状病毒的非洲小带喙果蝠(Epomophorus Labiatus)和寄主甲型冠状病毒的北美小褐肌蝙蝠(Myotis Lucifugus)的反应，将确定对甲型冠状病毒和乙型冠状病毒的共同耐受机制。一种强大的双重RNA测序方法将被部署，以同时对病毒体和宿主转录组进行测序。利用加权基因相关网络分析，基因表达计数将被用来确定宿主中与每个冠状病毒感染最密切相关的基因网络。将对这些相关的基因网络进行功能分析，以确定哪些免疫途径与CoV耐受性有关，要么通过阻断炎症和免疫激活，要么通过抑制组织损伤。最后，这些共同调控基因的功能将与在新宿主(人类和其他动物)中记录的功能进行比较。这一快速奖项是由综合组织系统生物部的生理和结构系统集群利用冠状病毒援助、救济和经济安全(CARE)法案的资金颁发的。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.