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Principal Investigator: Shyam Biswal
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2020
Award: $450,313
Funding agency: National Institute of Environmental Health Sciences
It is estimated that while the majority of SARS-CoV2 infections in the ongoing coronavirus disease-2019
(COVID-19) pandemic are asymptomatic or have mild symptoms, hospitalizations and mortality largely
occurs in patients with co-morbid conditions such as obesity, diabetes and COPD. Our understanding of
the role of environmental exposures in modifying the response to SARS-CoV2 is emerging and air
pollution; smoking and vaping have been associated with worst outcomes of SARS-CoV2 patients. There is
a time sensitive urgent need to understand host defense mechanisms which are compromised due to
environmental exposures and may increase susceptibility to SARS-CoV2 infection. This competing revision
will forge collaboration with expert in SARS-CoV2 research to expand our horizon in this critical area. We
will test the hypothesis of targeting a host defense pathway which is compromised in air pollution that may
protect and modify the response to SARS-COV2 respiratory infection. Through the parent U grant, we have
demonstrated that chronic exposure to PM2.5 has an overarching role in epigenetic reprogramming. Our
studies have established that transcription factor Nuclear factor erythroid-factor 2 (Nrf2) is a key activator of
anti-oxidative, anti-inflammatory, and innate immune defenses. We and others have demonstrated in
human biospecimens and animal models that chronic exposure to PM2.5 causes a decline in Nrf2 activity
that correlates with compromised innate immune defenses. In mice deficient for Nrf2 (Nrf2-/-), viral and
bacterial infection causes oxidative stress, worsened lung inflammation, acute lung injury and greater
mortality compared to wildtype mice. Genetic or pharmacological activation of Nrf2 pathway can rescue
these effects. Disruption of Nrf2 pathway has been shown to cause upregulation of angiotensin-converting
enzyme 2 (ACE2) which is the functional receptor for SARS-CoV2 entry into lung epithelial cells.
Furthermore, hypomethylation in ACE2 gene has been demonstrated to increase ACE2 expression in
immunocompromised patients. The goal for this project is to investigate the crosstalk of air pollution
exposure, host defense and SARS-CoV2 infection. Preclinical testing of therapeutic efficacy of Nrf2
activators will provide proof of concept for further development a novel drug target for prevention and
treatment of SARS-COV2 infection. The proposal will leverage expertise of our team on air pollution,
respiratory diseases and an expert virologist with ongoing BSL-3 SARS-CoV2 research. Successful
completion of this project will provide proof of concept for future studies directed towards development of a
novel strategy of targeting host defense for prevention and treatment of SARS-CoV2 infection in
susceptible populations.
Terms: <2019 novel coronavirus><2019-nCoV><Acute Lung Injury><Acute Pulmonary Injury><Affect><Air Pollution><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Animal Model><Animal Models and Related Studies><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatories><Antiinflammatory Agents><Apical><Area><Bacterial Infections><Basal Transcription Factor><Basal transcription factor genes><CD143 Antigens><COPD><COVID-19><COVID-19 epidemic><COVID-19 pandemic><COVID19><COVID19 epidemic><COVID19 pandemic><Caliber><Carboxycathepsin><Cardiopulmonary><Cell Body><Cell Communication><Cell Culture Techniques><Cell Death><Cell Interaction><Cell-to-Cell Interaction><Cells><Chemokine Receptor Gene><Chronic><Chronic Obstruction Pulmonary Disease><Chronic Obstructive Airway Disease><Chronic Obstructive Lung Disease><Chronic Obstructive Pulmonary Disease><Collaborations><DNA Methylation><Development><Diabetes Mellitus><Diameter><Dipeptidyl Peptidase A><Environmental Exposure><Environmental Factor><Environmental Risk Factor><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial><Epithelial Cells><Epithelium><Epithelium Part><Erythroid><Exposure to><Future><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genes><Genetic><Goals><Grant><Growth><Harvest><Hospital Admission><Hospitalization><Host Defense><Host Defense Mechanism><Human><Immune><Immunes><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunosuppressed Host><Infection><Inflammation><Kinetics><Kininase A><Kininase II><Lead><Lung><Lung Inflammation><Lung Respiratory System><Lung diseases><Measures><Mediating><Mice><Mice Mammals><Modern Man><Murine><Mus><Nuclear><Obesity><Outcome><Oxidative Stress><Parents><Particulate Matter><Pathway interactions><Patients><Pb element><Peptidyl-Dipeptidase A><Pharmacology><Population><Preclinical Testing><Predisposition><Prevention><Prevention therapy><Production><Pulmonary Diseases><Pulmonary Disorder><Receptor Protein><Research><Respiratory Disease><Respiratory Infections><Respiratory System Disease><Respiratory System Disorder><Respiratory Tract Infections><Role><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Severe acute respiratory syndrome coronavirus 2><Smoking><Study models><Susceptibility><Symptoms><Testing><Therapeutic><Time><Tissue Growth><Transcription Factor Proto-Oncogene><Transcription factor genes><Treatment Efficacy><Up-Regulation><Upregulation><Viral Diseases><Virus><Virus Diseases><Virus Replication><Vulnerable Populations><Wild Type Mouse><Wuhan coronavirus><adiposity><airway epithelium><antiinflammatory><bacteria infection><bacterial disease><cell culture><chemokine receptor><co-morbid><co-morbidity><comorbidity><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 epidemic><coronavirus disease 2019 pandemic><corpulence><corpulency><corpulentia><cytokine><developmental><diabetes><disease of the lung><disorder of the lung><environmental risk><genetic approach><genetic strategy><heavy metal Pb><heavy metal lead><immunosuppressed patient><improved><improved outcome><inflammation marker><inflammatory marker><intervention efficacy><lung disorder><mRNA Expression><model of animal><model organism><monolayer><mortality><mouse model><murine model><necrocytosis><new approaches><new drug target><new drug treatments><new druggable target><new drugs><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel approaches><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><obese><obese people><obese person><obese population><ontogeny><pathway><pre-clinical testing><protein expression><pulmonary><receptor><receptor expression><response><social role><therapeutic efficacy><therapeutically effective><therapy efficacy><transcription factor><vaping><viral infection><viral multiplication><viral replication><virus infection><virus multiplication><virus-induced disease><vulnerable group><wildtype mouse>