RAPID: Adaptive immunity in bats: foundational knowledge for assessing specific pathogen responses in natural coronavirus reservoirs

近年来，一些感染从非人类动物传染给人类，造成了许多不同的疾病，给公共卫生和经济造成了巨大的负担。特别是，目前的新冠肺炎大流行是由SARS-CoV-2引起的，这种冠状病毒的祖先可能是在非人类动物身上进化而来的。一般来说，蝙蝠携带着各种各样的冠状病毒。事实上，SARS-CoV-2，就像它的亲缘SARS-CoV一样，是导致SARS的病毒，被假设起源于蝙蝠宿主。这项拟议的研究试图了解病毒的自然宿主如何应对这些感染，并特别关注蝙蝠的免疫。蝙蝠是一个非常多样化的群体，与许多新出现的人类感染有关，但也提供关键的生态系统服务，如病虫害控制、种子传播和授粉。这项研究将阐明蝙蝠免疫如何塑造这些病毒的进化。这将为如何潜在地预防、管理或治疗人类感染以及保护和更好地了解蝙蝠提供见解。这项研究还将促进本科生在基因组实验室技术和生物信息学分析方面的培训，培养下一代科学家。目前，人们对蝙蝠免疫的了解有限，部分原因是蝙蝠物种的多样性，以及缺乏研究它们的免疫学试剂。特别是，大多数研究都集中在少数物种的天然免疫上；几乎对构成适应性免疫基础的免疫球蛋白和T细胞知之甚少。这项拟议的研究克服了这些障碍，使用基因组学方法来了解多种蝙蝠物种的适应性免疫。具体地说，拟议的研究将1)使用基因捕获、长阅读测序和定向扩增和测序相结合的方法，分析多种不同蝙蝠物种(包括已知冠状病毒宿主)的种系和重排的免疫球蛋白和T细胞受体谱；2)使用单细胞转录组分析参与适应性免疫的细胞的特征；以及3)测试野生蝙蝠中的冠状病毒，并比较感染和未感染蝙蝠之间的免疫球蛋白谱。这些结果将为一个重要的水库群适应性免疫提供基础知识，阐明蝙蝠与病原体在多个物种中的关系。其他人可以利用这些发现来描述蝙蝠对特定病原体的反应，预测某些物种是否具备更好的应对感染的能力，并指导人畜共患病的预防和干预工作。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。

In recent years a number of infections have passed from non-human animals to humans causing numerous different diseases and creating significant burdens on public health and the economy. In particular, the current COVID-19 pandemic is caused by SARS-CoV-2, a coronavirus whose ancestors likely evolved in a non-human animal. In general, bats host a wide diversity of coronaviruses. Indeed, SARS-CoV-2, like its relative SARS-CoV, the virus that causes SARS, is hypothesized to have its origins in bat hosts. The proposed research seeks to understand how the natural hosts of viruses respond to these infections with a specific focus on bat immunity. Bats are a hugely diverse group that have been linked to numerous emerging human infections but also provide critical ecosystem services such as pest control, seed dispersal and pollination. The research will clarify how bat immunity has shaped the evolution of these viruses. This will yield insights into how to potentially prevent, manage or treat infections in people, as well as protect and better understand bats. The research will also facilitate the training of undergraduate students in genomic laboratory techniques and bioinformatic analysis, training the next generation of scientists. Currently, there is a limited understanding of bat immunity, hampered in part by the diversity of bat species and lack of immunological reagents for studying them. In particular, most research has focused on innate immunity in a few species; almost nothing is known about the immunoglobulins and T cells that form the basis of adaptive immunity. The proposed research overcomes these obstacles by using genomic methods to understand adaptive immunity in multiple bat species. Specifically, the proposed research will 1) analyze the germline and rearranged immunoglobulin and T cell receptor repertoires in multiple, diverse bat species, including known coronavirus hosts, using a mix of gene capture, long-read sequencing, and targeted amplification and sequencing; 2) characterize the cells involved in adaptive immunity using single-cell transcriptomics; and 3) test for coronaviruses in wild bats and compare the immunoglobulin repertoire between infected and uninfected bats. The results will provide foundational knowledge of adaptive immunity of an important reservoir group, clarifying the bat-pathogen relationship in multiple species. These findings can be leveraged by others to characterize the responses of bats to specific pathogens, to predict whether certain species are better equipped to respond to infection, and to guide prevention and intervention efforts for zoonotic disease. 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.