CORALE-SeroNet Project 2

ABSTRACT Project 2 Project 2 of this U54 application is co-lead by Michael Karin (communicating PI) and Moshe Arditi (co-PI). This project will investigate the effect of pre-infection co-morbidities on the clinical outcome of SARS-Cov-2 infection. The novel severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, the causal agent of COVID-19 can establish lower airway infections. In a subset of patients, characterized by old age and a number of preexisting conditions and co-morbidities, these infections result in acute respiratory distress syndrome (ARDS). ARDS and its associated cytokine storm have been frequently observed in ICU admitted COVID-19 patients and are considered to be the leading causes of death in that group. The factors that determine which COVID-19 patients will develop ARDS and which will only have mild symptoms are poorly understood. Nonetheless, extensive correlative evidence indicate that pre-existing conditions including obesity, type 2 diabetes mellitus (T2DM), non- alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD), all of which are associated with elevated cancer risk, as well as primary lung and liver cancers and different metastatic cancers, greatly increase the likelihood of severe COVID-19 manifestations (ARDS, cytokine storm, massive coagulation disorder) and even death. Some of these risk factors may also account for the marked racial/ethnic disparity in COVID-19 mortality. Whereas the cause of death in patients undergoing ARDS is relatively well understood and related to enhanced production of inflammatory cytokines, the mechanisms by which the risk factors listed above act are poorly understood. In this project we will explore the overarching hypothesis that all COVID-19 enhancing risk factors/co-morbidities cause chronic low-grade inflammation, manifested by elevated IL-6 and C reactive protein, that leads to epigenetic changes in circulating monocytes and tissue macrophages. We will use peripheral blood mononuclear cells collected by Project 1 and CORE 1: Recruitment and Biobanking Core (RBC) to explore and test this hypothesis through the following aims: Aim 1: Compare activation thresholds and magnitude of cytokine production in PBMC isolated from uninfected study participants without or with pre-existing co- morbidities. Aim 2: Determine effect of pre-existing co-morbidities on epigenetic modifications of key inflammation controlling genes. Aim 3: Determine whether long-term use of metformin and statins prevents the epigenetic modifications associated with enhanced production of inflammatory cytokines. Aim 4: Assess if induction of trained immunity by BCG vaccination reduces the incidence and severity of SARS-CoV-2 infection through epigenetic, transcriptional and functional reprograming of monocytes/macrophages in individuals with and without various co-morbidities. We postulate that BCG vaccination alters the monocyte/macrophage epigenome to enhance their anti-viral and immunostimulatory functions to successfully clear SARS-CoV-2 infections and prevent their progression to ARDS and a cytokine storm in individuals without pre-existing co- morbidities but not in those with pre-existing co-morbidities.