RAPID: Collaborative Research: Bat goblet cells as immuno-hotspots for infection of coronavirus

为什么蝙蝠很可能携带冠状病毒，但似乎很少受到它们的影响？许多研究都集中在它们的免疫系统上，但关于病毒入侵时攻击的细胞，还有很多需要了解的。COVID-19人类患者的急性呼吸道症状以及奇怪的嗅觉丧失暗示，鼻道细胞首先受到影响。事实上，在鼻子里产生粘液的细胞，被称为杯状细胞，已经被证明是病毒进入的“起点”。由于这些细胞也存在于蝙蝠的鼻子中，因此冠状病毒攻击蝙蝠和人类杯状细胞的方式一定有所不同。然而，对蝙蝠杯状细胞中的免疫相关蛋白几乎一无所知。该项目提出了一种新的方法来了解蝙蝠如何抵抗呼吸道病毒，如与SARS-CoV-2相关的呼吸道病毒。通过对蝙蝠上呼吸道（鼻子和咽部）的解剖学和生理学进行多维度研究，这项工作将使研究人员能够更好地了解病毒是如何进入人体并感染或不感染宿主的。该项目还将使世界各地的卫生机构能够更好地调查蝙蝠种群，防止未来出现类似COVID-19的大流行。此外，该提案还支持研究生和博士后增加STEM领域的培训。获得该奖项支持的研究人员将验证一种假设，即鼻子解剖结构与人类相似的蝙蝠的呼吸道内壁具有特定的成分，这种成分的进化是为了防止SARS-CoV-2等病毒感染它们。为了了解与人类相比，蝙蝠的衬里或上皮是如何改变的，这笔拨款将把蝙蝠的蛋白质、DNA和组织学与人类和小鼠进行比较。这项工作将强调杯状细胞的作用，杯状细胞不仅产生粘液，而且具有免疫和炎症功能，对于感染抵抗病毒攻击至关重要。该团队还将整合从3D成像到蛋白质组学的多层数据，以构建蝙蝠上呼吸道内部和外部工作的完整图像。通过高分辨率的解剖可视化和揭示蝙蝠鼻道内壁产生的特定蛋白质，该项目将对蝙蝠的上呼吸道进行最彻底的研究。这对人类抗击人畜共患病毒和监测野生动物种群至关重要。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。

Why are bats so likely to carry coronaviruses, yet seem little affected by them? Many studies have focused on their immune system, but there is much to learn about the cells viruses attack upon entry. Acute respiratory symptoms, as well as the curious loss of the sense of smell in human patients with COVID-19 hint that cells in the nasal passage are afflicted first. Indeed, cells that produce mucus in the nose, known as goblet cells, have been shown to be “ground zero” for viral entry. Since these cells are also present in bat noses, there must be a difference in how coronaviruses attack goblet cells in bats versus humans. However, virtually nothing is known about immune-related proteins in bat goblet cells. This project proposes a new approach to understand how bats are resistant to respiratory viruses such as those related to SARS-CoV-2. By generating a multi-dimensional study of the anatomy and physiology of the upper respiratory tract —nose and pharynx— of bats, the proposed work will enable researchers to better understand how viruses enter the body and infect or fail to infect their hosts. This project will also allow health agencies around the world to better survey bat populations and prevent future pandemics similar to COVID-19. In addition, this proposal supports a graduate student and post-doctoral fellow to increase training in STEM fields. Researchers supported by this award will test the hypothesis that bats with nasal anatomy similar to humans have a specific composition of the lining of their respiratory tract, evolved to prevent viruses such as SARS-CoV-2, from infecting them. To understand how the lining, or epithelium, is modified in bats compared to humans, this grant will compare the proteins, DNA, and histology of bats to humans and mice. The proposed work will highlight the role of goblet cells, which do not only produce mucus, but also have immune and inflammatory functions, as critical for infection from- versus resistance to viral attack. The team will also integrate layers of data, from 3D imaging to proteomics, to build a complete picture of the inner and outer workings of the upper respiratory tracts of bats. By visualizing the anatomy in high resolution and uncovering which specific proteins are produced by the lining of the bat’s nasal passage, this project will produce the most thorough study of the upper respiratory tracts of bats yet. This will be critical for humanity’s fight against zoonotic viruses, and surveillance of wildlife populations. 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.