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Principal Investigator: Murugappan Ramanathan
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2020
Award: $196,500
Funding agency: National Institute of Allergy and Infectious Diseases
Program Director/Principal Investigator (Last, First, Middle): Ramanathan, Murugappan Jr
It is estimated that while the majority of SARS-CoV-2 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-CoV-2 is emerging and air
pollution, smoking and vaping have been associated with worst outcomes of SARS-CoV-2 patients. There
is a time sensitive urgent need to understand host defense mechanisms in the sinonasal epithelia which
are compromised due to environmental exposures and may increase susceptibility to SARS-CoV-2
infection. This administrative supplement will forge collaboration with an expert in SARS-CoV-2 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-COV-2
respiratory infection. Through the parent R01 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 airway epithelial cells. Furthermore, hypomethylation of the ACE2 gene has
been demonstrated to increase ACE2 expression in immunocompromised patients. The goal for this
administrative supplement (in response to NOT-AI-020-031) is to investigate the crosstalk of air
pollution exposure, host defense and SARS-CoV-2 infection. If this pilot project is successful,
preclinical testing of Nrf2 activators will provide proof of concept for further development a novel
drug target for prevention and treatment of SARS-CoV-2 infection. The proposal will leverage
expertise of our team on air pollution, respiratory diseases and an expert virologist with ongoing BSL-3
SARS-CoV-2 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-CoV-2 infection in susceptible populations.
Terms: <2019 novel coronavirus><2019-nCoV><Acute Lung Injury><Acute Pulmonary Injury><Administrative Supplement><Air Pollution><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Animal Model><Animal Models and Related Studies><Anosmia><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><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><Data><Development><Diabetes Mellitus><Diameter><Dipeptidyl Peptidase A><Disease><Disorder><Dysfunction><Environmental Exposure><Environmental Factor><Environmental Risk Factor><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial><Epithelial Cells><Epithelium><Epithelium Part><Erythroid><Exposure to><Functional disorder><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><Nasal><Nasal Passages Nose><Nose><Nuclear><Obesity><Outcome><Oxidative Stress><Parents><Particulate Matter><Pathway interactions><Patients><Pb element><Peptidyl-Dipeptidase A><Pharmacology><Physiopathology><Pilot Projects><Population><Preclinical Testing><Predisposition><Prevention><Prevention therapy><Principal Investigator><Production><Pulmonary Diseases><Pulmonary Disorder><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Research><Respiratory Disease><Respiratory Infections><Respiratory System Disease><Respiratory System Disorder><Respiratory System, Nose, Nasal Passages><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><Viral Diseases><Virus><Virus Diseases><Virus Replication><Vulnerable Populations><Wild Type Mouse><Wuhan coronavirus><adiposity><airway epithelium><anosphrasia><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><efficacy testing><environmental risk><epigenomics><exposed human population><heavy metal Pb><heavy metal lead><human exposure><immunosuppressed patient><improved><improved outcome><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><pathophysiology><pathway><pilot study><pre-clinical testing><programs><protein expression><pulmonary><receptor><receptor expression><respiratory><response><social role><therapeutic efficacy><therapeutically effective><therapy efficacy><transcription factor><transcriptome sequencing><vaping><viral infection><viral multiplication><viral replication><virus infection><virus multiplication><virus-induced disease><vulnerable group><wildtype mouse>