Transcriptional and non-transcriptional functions of IRF3 in ALD

Abstract: Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a highly contagious and fast-spreading infectious disease, which reached pandemic status in only fourmonths and is spreading worldwide with millions of people being affected. The clinical spectrum of COVID-19ranges from mild to critically ill diseases. COVID-19 can progress rapidly into acute respiratory distress syndrome(ARDS), multiorgan failure, and even death. In the midst of the COVID-19 epidemic, there is some evidence forincreased alcohol purchases. Since people generally buy more alcohol during epidemics, increased alcoholconsumption may result in reduced resistance to infections like COVID-19 and promote the progression of thedisease. SARS-COV-2 is a positive-sense single stranded RNA (ssRNA). While alcohol consumption has notyet been shown to directly increase risk for SARS-COV-2 transmission or COVID-19 severity, alcohol negativelyaffects the both the innate and adaptive immune systems and increases risk for many infectious diseases.Importantly, recent data from both murine models of ethanol exposure and peripheral blood mononuclear cells(PBMCs) from patients with alcohol-associated hepatitis (AH) indicate that signaling by viral ss/dsRNA isdisrupted by alcohol, analogous to impact of alcohol on signaling via bacterial products, such as LPS. The parentRO-1 (Transcriptional and non-transcriptional roles of IRF3 in ALD) for this URGENT COMPETITIVE RENEWAL,we are investigating the impact of chronic ethanol on ss/ds RNA sensing and activation of IRF3-mediated cellularresponses. Here we propose to extend the scope of this RO1 to address two important aspects of the interactionof alcohol and COVID-19 in people consuming alcohol. In Specific Aim 1, making use of data from the UKBiobank, we will ask whether alcohol consumption or alcohol-related diseases increase risk of infection,hospitalization and mortality. In Specific Aim 2, we will use single cell RNA seq analysis to interrogate the impactof alcohol consumption on anti-viral responses in peripheral innate and adaptive immune cells. Understandingthe impact of alcohol use on risk for COVID-19 and characterizing the specific cellular changes in anti-viralresponses will meet an important unmet clinical need for guiding public health and medical responses to theCOVID-19 pandemic.