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Principal Investigator: Noah M Merin
Organization: CEDARS-SINAI MEDICAL CENTER
Fiscal Year: 2022
Award: $402,829
Funding agency: National Cancer Institute
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.
Terms: <(IFN) α><(IFN)-α><(IFN)α><(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><3-10C><65+ years old><AMCF-I><ARDS><ATAC-seq><ATACseq><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Adult-Onset Diabetes Mellitus><Age><Aged 65 and Over><Airway infections><Alferon><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-diabetic Agents><Anti-inflammatory><Antidiabetic Agents><Antidiabetic Drugs><Antiinflammatories><Antiinflammatory Agents><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BCG immunization><BCG vaccination><BCG-vaccinated><BSF-2><BSF2><Bacille Calmette-Guerin vaccinated><Bacille Calmette-Guerin vaccination><Bacillus Calmette-Guerin vaccination><Bacillus Calmette-Guérin vaccination><Beta Proprotein Interleukin 1><Blood Coagulation Disorders><Blood monocyte><Body Tissues><C-reactive protein><COVID disease severity><COVID disparity><COVID infected patient><COVID patient><COVID positive patient><COVID related disparity><COVID severity><COVID-19><COVID-19 S protein><COVID-19 associated death><COVID-19 associated fatality><COVID-19 associated mortality><COVID-19 death><COVID-19 disease severity><COVID-19 disparity><COVID-19 fatality><COVID-19 induced death><COVID-19 induced disparity><COVID-19 induced fatality><COVID-19 induced mortality><COVID-19 infected patient><COVID-19 infection><COVID-19 mortality><COVID-19 patient><COVID-19 positive patient><COVID-19 related death><COVID-19 related disparity><COVID-19 related fatality><COVID-19 related mortality><COVID-19 severity><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID19><COVID19 S protein><COVID19 associated death><COVID19 associated fatality><COVID19 associated mortality><COVID19 death><COVID19 disease severity><COVID19 disparity><COVID19 fatality><COVID19 induced death><COVID19 induced fatality><COVID19 induced mortality><COVID19 infection><COVID19 mortality><COVID19 patient><COVID19 positive patient><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 severity><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><CSIF><CSIF-10><CV-19><CV19><CXCL8><Cachectin><Cancers><Cardiovascular Diseases><Cause of Death><Cell Communication and Signaling><Cell Signaling><Cessation of life><ChIP Sequencing><ChIP-seq><Chronic><Clinical><CoV-2><CoV2><Coagulation Disorder><Coagulopathy><Control Groups><Cytokine Synthesis Inhibitory Factor><DNA Methylation><Da Nang Lung><Death><Dimethylbiguanidine><Dimethylguanylguanidine><Disease><Disorder><Disseminated Malignant Neoplasm><Dose><Edodekin Alfa><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial Cells><Ethnic Origin><Ethnicity><Experimental Designs><GCP1><GM-CSF><Gamma interferon><Gender><Gene Transcription><Genes><Genetic Transcription><Granulocyte-Macrophage Colony-Stimulating Factor><HPGF><Health Care Providers><Health Personnel><Healthcare Providers><Healthcare worker><Hepatic Cancer><Hepatocyte-Stimulating Factor><Heritability><Histamine-Producing Cell-Stimulating Factor><Hybridoma Growth Factor><IFN><IFN Alpha><IFN α><IFN-Gamma><IFN-beta 2><IFN-g><IFN-gamma-Inducing Factor><IFN-α><IFN-γ><IFNB2><IFNG><IFNa><IFNα><IFNγ><IGIF><IL-1 Gamma><IL-1 alpha><IL-1 beta><IL-1 β><IL-1-a><IL-1-b><IL-10><IL-12><IL-18><IL-1A><IL-1alpha><IL-1g><IL-1α><IL-1β><IL-23><IL-6><IL-7><IL-7 Gene><IL-8><IL1-Alpha><IL1-Beta><IL1-α><IL1-β><IL10><IL10A><IL12><IL18 Protein><IL1A Protein><IL1B Protein><IL1F1><IL1F2><IL1F4><IL1β><IL6 Protein><IL7><IL7 Protein><IL7 gene><IL8><IL8 gene><Immune><Immune Interferon><Immunes><Immunity><Incidence><Individual><Infection><Inflammasome><Inflammation><Inflammatory><Inflammatory Response><Innate Immunity><Interferon Alfa-n3><Interferon Gamma><Interferon Type II><Interferon-alpha><Interferon-gamma><Interferon-gamma-Inducing Factor><Interferon-α><Interferons><Interleukin 10 Precursor><Interleukin 18 (Interferon-Gamma-Inducing Factor)><Interleukin 18 Proprotein><Interleukin 1alpha><Interleukin 1beta><Interleukin 7 Precursor><Interleukin 7 Precursor Gene><Interleukin-1 Gamma><Interleukin-1 alpha><Interleukin-1 beta><Interleukin-10><Interleukin-12><Interleukin-18><Interleukin-18 Precursor><Interleukin-1β><Interleukin-6><Interleukin-7><Interleukin-7 Gene><Intracellular Communication and Signaling><K60><Ketosis-Resistant Diabetes Mellitus><Lead><Leukocyte Interferon><Ligands><Link><Lung><Lung Respiratory System><Lymphoblast Interferon><Lymphoblastoid Interferon><Lymphopoietin-1><MGC12320><MGI-2><Macrophage-Derived TNF><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of liver><Malignant neoplasm of lung><Marrow monocyte><Maturity-Onset Diabetes Mellitus><Measures><Mediating><Metastatic Cancer><Metastatic Malignant Neoplasm><Metformin><Methodology><Modification><Molgramostin><Monocyte-Derived TNF><Myeloid Differentiation-Inducing Protein><Mφ><N,N-dimethyl-imidodicarbonimidic diamide><NAFLD><NIDDM><NKSF><Native Immunity><Natural Immunity><Natural Killer Cell Stimulatory Factor><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Non-Polyadenylated RNA><Non-Specific Immunity><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nonspecific Immunity><Obesity><Outcome><PBMC><Participant><Patients><Pb element><Peripheral Blood Mononuclear Cell><Plasmacytoma Growth Factor><Preinterleukin 1 Alpha><Preinterleukin 1 Beta><Production><Proteins, specific or class, C-reactive><Pulmonary Cancer><Pulmonary malignant Neoplasm><RNA><RNA Expression><RNA Gene Products><RNA Seq><RNA sequencing><RNAseq><Race><Racial Group><Racial Stocks><Receptor Signaling><Research Specimen><Respiratory Infections><Respiratory Tract Infections><Ribonucleic Acid><Risk><Risk Factors><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 associated death><SARS-CoV-2 associated fatality><SARS-CoV-2 associated mortality><SARS-CoV-2 death><SARS-CoV-2 disease severity><SARS-CoV-2 fatality><SARS-CoV-2 induced death><SARS-CoV-2 induced fatality><SARS-CoV-2 induced mortality><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 mortality><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 related death><SARS-CoV-2 related fatality><SARS-CoV-2 related mortality><SARS-CoV-2 severity><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 infection><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SCYB8><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Shock Lung><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Specimen><Stable Diabetes Mellitus><Stiff lung><Symptoms><T2 DM><T2D><T2DM><TC-GM-CSF><TLR protein><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><TSG-1><Testing><Tissues><Toll-Like Receptor Family Gene><Toll-like receptors><Training><Transcription><Trioxopurine><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Tumor-Cell Human GM Colony-Stimulating Factor><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Uric Acid><Viral><Wuhan coronavirus><adiposity><adult onset diabetes><age 65 and greater><age 65 and older><aged 65 and greater><aged ≥65><ages><analytical method><anti-diabetic><anti-diabetic drugs><antidiabetic><antiinflammatory><attenuation><b-ENAP><biobank><biological signal transduction><biorepository><bleeding disorder><cancer risk><cardiovascular disorder><chromatin immunoprecipitation-sequencing><clotting disorder><co-infection><co-morbid><co-morbidity><cohort><coinfection><comorbidity><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 associated death><coronavirus disease 2019 associated fatality><coronavirus disease 2019 associated mortality><coronavirus disease 2019 death><coronavirus disease 2019 disease severity><coronavirus disease 2019 disparity><coronavirus disease 2019 fatality><coronavirus disease 2019 induced death><coronavirus disease 2019 induced fatality><coronavirus disease 2019 induced mortality><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 mortality><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 related death><coronavirus disease 2019 related fatality><coronavirus disease 2019 related mortality><coronavirus disease 2019 severity><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease severity><coronavirus disease-19><coronavirus disease-19 mortality><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><corpulence><cytokine><cytokine release syndrome><cytokine storm><death due to COVID-19><death due to COVID19><death due to SARS-CoV-2><death due to coronavirus disease 2019><death due to severe acute respiratory syndrome coronavirus 2><death in COVID><death in COVID-19><death in SARS-CoV-2><death in coronavirus disease><death in coronavirus disease 2019><death in severe acute respiratory syndrome coronavirus 2><disparities in COVID><disparities in COVID-19><disparity due to COVID-19><epigenome><ethnoracial disparities><fatality due to COVID-19><fatality due to COVID19><fatality due to SARS-CoV-2><fatality due to coronavirus disease 2019><fatality due to severe acute respiratory syndrome coronavirus 2><genome scale><genome-wide><genomewide><granulocyte macrophage colony stimulating factor><hCoV19><health care personnel><health care worker><health provider><health workforce><healthcare personnel><heavy metal Pb><heavy metal lead><high risk><human old age (65+)><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><interferon beta 2><interleukin-23><ketosis resistant diabetes><lFN-Gamma><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><liver cancer><liver malignancy><lung cancer><macrophage><malignancy><malignant liver tumor><maturity onset diabetes><medical personnel><member><monocyte><mortality due to COVID-19><mortality due to COVID19><mortality due to SARS-CoV-2><mortality due to coronavirus disease 2019><mortality due to severe acute respiratory syndrome coronavirus 2><nCoV2><negative affect><negative affectivity><neoplasm/cancer><neuroinflammation><neuroinflammatory><non-alcohol fatty liver disease><non-alcoholic fatty liver disease><non-alcoholic liver disease><nonalcoholic fatty liver disease><novel><old age><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient subgroups><patient subpopulations><patient subsets><patient subtypes><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><prevent><preventing><pulmonary><racial and ethnic disparities><recruit><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 associated death><severe acute respiratory syndrome coronavirus 2 associated fatality><severe acute respiratory syndrome coronavirus 2 associated mortality><severe acute respiratory syndrome coronavirus 2 death><severe acute respiratory syndrome coronavirus 2 disease severity><severe acute respiratory syndrome coronavirus 2 fatality><severe acute respiratory syndrome coronavirus 2 induced death><severe acute respiratory syndrome coronavirus 2 induced fatality><severe acute respiratory syndrome coronavirus 2 induced mortality><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 mortality><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 related death><severe acute respiratory syndrome coronavirus 2 related fatality><severe acute respiratory syndrome coronavirus 2 related mortality><severe acute respiratory syndrome coronavirus 2 severity><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><transcriptome sequencing><treatment provider><type 2 DM><type II DM><type two diabetes><wet lung>