# Enhanced infectivity of SARS-CoV-2 in Particulate Matter exposed Sinonasal Epithelial Cells

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $196,500

## Abstract

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.

## Key facts

- **NIH application ID:** 10169918
- **Project number:** 3R01AI143731-02S1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Murugappan Ramanathan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $196,500
- **Award type:** 3
- **Project period:** 2020-06-17 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10169918

## Citation

> US National Institutes of Health, RePORTER application 10169918, Enhanced infectivity of SARS-CoV-2 in Particulate Matter exposed Sinonasal Epithelial Cells (3R01AI143731-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10169918. Licensed CC0.

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