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

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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.