RAPID: Biomimicry of SARS-CoV-2 and its consequences for infectivity and inflammation

这项研究解决了两个关于严重急性呼吸综合征冠状病毒2(SARS-CoV-2)的关键问题：为什么这种病毒如此具有传染性，以及为什么它有时会引起致命的炎症？现在众所周知，新冠肺炎感染可以在症状出现之前从宿主传播，这意味着病毒有效地进入和输出。新冠肺炎引起炎症的根本原因鲜为人知，但在其他超级病毒中也看到了类似的影响，如最初的严重急性呼吸综合征冠状病毒和1918年大流行的流感病毒。这项研究调查了这种病毒部分如何模仿人类先天性免疫系统中防御分子的功能的基本分子机制，这些防御分子重组膜和控制炎症，从而使病毒能够实现上述两种效果。这项研究的多学科性质也将为学生提供多层次的培训机会。该项目的总体目标是利用人工智能、基础生物物理学、免疫学和病毒学进行基础研究，这些研究可能有助于缓解当前的新冠肺炎危机。项目目标有两个方面。1：使用机器学习方法识别SARS-CoV-2病毒基因组中编码的分子，这些分子重塑病毒进入和脱落的膜，并通过模仿蝙蝠中发现的分子来设计关闭这一活动的方法，蝙蝠携带许多冠状病毒，因此对它们有更进化的防御系统。2：识别SARS-CoV-2病毒的分子，这些分子模仿人类先天免疫系统的分子，已知这些分子介导了强大的炎症反应，从而允许潜在的下游分子设计方法来缓解这种类型的炎症。这些想法将通过在美国最先进的第三代同步辐射设施中进行的小角X射线散射(SAXS)实验以及传统的免疫学和抗病毒实验来测试，包括在设计用于应对SARS-CoV-2的高密封性生物安全3级设施中进行的那些实验。这一基础研究项目的预期结果可以为新冠肺炎治疗策略的设计提供翻译指导，即使当前的候选疫苗失败了。这个快速奖项是由分子和细胞生物科学部门的细胞动力学和功能计划利用冠状病毒援助、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。

This research addresses two critically important questions concerning the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes the novel coronavirus disease (COVID-19): Why is this virus so infectious, and why does it sometimes cause lethal inflammation? It is now well-known that COVID-19 infections can spread from hosts early, before onset of symptoms, which implies efficient viral entry and egress. The root causes of COVID-19 induced inflammation are less known, but cognate effects have been seen in other superviruses such as the coronavirus for the original severe acute respiratory syndrome (SARS), and the 1918 pandemic influenza virus. This research investigates the basic molecular mechanisms of how parts of this virus can mimic the functions of defensive molecules from the human innate immune system which restructure membranes and control inflammation, thereby allowing the virus to achieve both of the above effects. The multidisciplinary nature of the research will also provide training opportunities for students at multiple levels. The overall goal of this project is to perform basic research that may help mitigate the current COVID-19 crisis by using artificial intelligence informed fundamental biophysics, immunology, and virology. The project objectives are two-fold. 1: use machine learning methods to identify molecules encoded in the genome of the SARS-CoV-2 virus that remodel the membrane for viral entry and viral shedding, and design ways to turn off this activity by mimicking molecules found in bats, which harbor many coronaviruses and therefore have more evolved defenses against them. 2: Identify molecules from the SARS-CoV-2 virus that mimic molecules from the human innate immune system which are known to mediate potent inflammatory responses, thus allowing potential downstream design of molecular approaches to alleviate this type of inflammation. These ideas will be tested using small angle x-ray scattering (SAXS) experiments performed at state-of-the-art 3rd generation synchrotron radiation facilities in the US, as well as traditional immunological and antiviral experiments, including those done at high containment biosafety level 3 facilities designed to handle SARS-CoV-2. Expected results from this basic research project can provide translational guidance for design of COVID-19 treatment strategies, even if current vaccine candidates fail. This RAPID award is made by the Cellular Dynamics and Function Program in the Division of Molecular and Cellular Biosciences, 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.