Mechanism of BET Proteins in Th17 Cell Differentiation

This administrative supplement application is submitted for the parent award (5R01AI124465) inresponse to NIAID's Notice of Special Interest (NOT-AI-20-031) "Severe Acute Respiratory SyndromeCoronavirus (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19)", as well as "AdministrativeSupplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp - Clinical TrialOptional)" (PA-18-591). The outbreak of the new coronavirus (SARS-CoV-2) infection is spreading toevery continent around the world at an astonishing speed. As of April 15, 2020, coronavirus disease2019 (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 tostop the rapid spread of SARS-CoV-2 infection in this devastating pandemic. While current focus is ondeveloping novel therapeutics including antivirals and vaccines, mounting evidence show that manysevere 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 majorunmet medical need. Clinically, host cells elicit two-phased responses to SARS-CoV-2 infection. Inan early incubation and non-severe stage, immune cells such as macrophages detect the virus andproduce cytokines to eliminate the virus. But, when a protective immune response is impaired, thevirus propagates, and the disease is transitioned to a severe stage where innate inflammation isinduced by virus-caused massive tissue damage with uncontrolled cytokine release (aka CytokineStorm) from inflammatory macrophages and granulocytes, resulting in ARDS in the lungs. Ascendedpro-inflammatory cytokines such as IL-6, IL-10, IL-17, GM-CSF, MCP-1, IFN-γ, and TNF-α arereported in severe COVID-19 patients. Lung hyper-inflammation is the main cause of life-threateningrespiratory disorders at the severe stage. Notably, our study shows that transcriptional activation ofthese inflammatory cytokines is directed by major transcription factors NF-kB and STAT3 in concertwith chromatin regulators BRD2 and BRD4, and that their activities can be effectively blocked bychemical inhibitors. Motivated by our findings, in this study, we propose to identify and repurposeFDA-approved drugs to suppress SARS-CoV-2-induced cytokine storm through simultaneouslyblocking NF-kB and STAT3 signaling pathways. We will achieve this goal by addressing the twospecific aims: (1) identify FDA-approved drugs to block uncontrolled cytokine release induced bySARS2-CoV-2; (2) validate chemical inhibition of hyperinflammation in human immune cell linesincluding human peripheral blood mononuclear cells from COVID-19 patients.