The role of pattern recognition and autophagy in innate anti-bunyaviral immunity

The current outbreak of the coronavirus in China (SARS-CoV-2) has spread rapidly. There are experimental drugswhich will be tested; however, there are no approved therapeutics or vaccines. Indeed, there are tests underway todetermine whether remdesivir, which was developed against filoviruses, can be repurposed against SARS-CoV-2infection. It would be transformative if we could identify additional small molecules that could be repurposed to treatthe outbreak of SARS-CoV-2 infection. Given that the goal of the parent grant (R01AI150246) is to discoverantivirals active against bunyaviruses, based on findings from cell based screening, and that we have broadexpertise in diverse viruses, we are applying for Supplemental funding (notice number NOT-AI-20-030, PA-18-035)to expand the scope of the existing grant to use the same methods (small molecule screening) to identify antiviraltherapeutics active against SARS-CoV-2 infection. We will screen two libraries of known bioactives to potentiallyrepurpose existing therapeutics. First, we will test a library of innate immune agonists (~100 PAMPs) for their abilityto block SARS-CoV-2 infection in human cells including airway cells. Second, we will screen another 'actionable'library that I have created as the Director of the High-throughput Screening core at UPENN. We created a library of~3000 drugs that includes ~1500 FDA approved compounds, ~1000 drugs in clinical trials and the remaining drugshave known targets. This library has been used for repurposing (as is being done with the Gilead drug remdesivirthat was originally developed against filoviruses) to more rapidly identify active therapeutics for future testing inhumans. We will also determine if any of our active antivirals act synergistically with remdesivir since this drug iscurrently under development for use against COVID-19. We expect to identify additional drugs with activity againstSARS-CoV-2.