PROJECT SUMMARY This administrative supplement application is submitted for the parent award (5R01AI124465) in response to NIAID’s Notice of Special Interest (NOT-AI-20-031) “Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19)”, as well as “Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp - Clinical Trial Optional)” (PA-18-591). The outbreak of the new coronavirus (SARS-CoV-2) infection is spreading to every continent around the world at an astonishing speed. As of April 15, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 2,035,764 people worldwide, causing a mortality of 6.42%, exceeding far beyond a mortality rate of <1% from influenza. Effective treatment is urgently needed to stop the rapid spread of SARS-CoV-2 infection in this devastating pandemic. While current focus is on developing novel therapeutics including antivirals and vaccines, mounting evidence show that many severe COVID-19 patients suffer from respiratory failure by acute respiratory distress syndrome (ARDS), the leading cause of COVID-19 mortality. In this study, we aim to address this major unmet medical need. Clinically, host cells elicit two-phased responses to SARS-CoV-2 infection. In an early incubation and non-severe stage, immune cells such as macrophages detect the virus and produce cytokines to eliminate the virus. But, when a protective immune response is impaired, the virus propagates, and the disease is transitioned to a severe stage where innate inflammation is induced by virus-caused massive tissue damage with uncontrolled cytokine release (aka Cytokine Storm) from inflammatory macrophages and granulocytes, resulting in ARDS in the lungs. Ascended pro-inflammatory cytokines such as IL-6, IL-10, IL-17, GM-CSF, MCP-1, IFN-γ, and TNF-α are reported in severe COVID-19 patients. Lung hyper-inflammation is the main cause of life-threatening respiratory disorders at the severe stage. Notably, our study shows that transcriptional activation of these inflammatory cytokines is directed by major transcription factors NF-kB and STAT3 in concert with chromatin regulators BRD2 and BRD4, and that their activities can be effectively blocked by chemical inhibitors. Motivated by our findings, in this study, we propose to identify and repurpose FDA-approved drugs to suppress SARS-CoV-2-induced cytokine storm through simultaneously blocking NF-kB and STAT3 signaling pathways. We will achieve this goal by addressing the two specific aims: (1) identify FDA-approved drugs to block uncontrolled cytokine release induced by SARS2-CoV-2; (2) validate chemical inhibition of hyperinflammation in human immune cell lines including human peripheral blood mononuclear cells from COVID-19 patients.