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

Program Director/Principal Investigator (Last, First, Middle): Ramanathan, Murugappan JrIt 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 largelyoccurs in patients with co-morbid conditions such as obesity, diabetes and COPD. Our understanding ofthe role of environmental exposures in modifying the response to SARS-CoV-2 is emerging and airpollution, smoking and vaping have been associated with worst outcomes of SARS-CoV-2 patients. Thereis a time sensitive urgent need to understand host defense mechanisms in the sinonasal epithelia whichare compromised due to environmental exposures and may increase susceptibility to SARS-CoV-2infection. This administrative supplement will forge collaboration with an expert in SARS-CoV-2 research toexpand our horizon in this critical area. We will test the hypothesis of targeting a host defense pathwaywhich is compromised in air pollution that may protect and modify the response to SARS-COV-2respiratory infection. Through the parent R01 grant, we have demonstrated that chronic exposure to PM2.5has an overarching role in epigenetic reprogramming. Our studies have established that transcription factorNuclear factor erythroid-factor 2 (Nrf2) is a key activator of anti-oxidative, anti-inflammatory, and innateimmune defenses. We and others have demonstrated in human biospecimens and animal models thatchronic exposure to PM2.5 causes a decline in Nrf2 activity that correlates with compromised innateimmune 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 orpharmacological activation of Nrf2 pathway can rescue these effects. Disruption of Nrf2 pathway has beenshown to cause upregulation of angiotensin-converting enzyme 2 (ACE2) which is the functional receptorfor SARS-CoV2 entry into airway epithelial cells. Furthermore, hypomethylation of the ACE2 gene hasbeen demonstrated to increase ACE2 expression in immunocompromised patients. The goal for thisadministrative supplement (in response to NOT-AI-020-031) is to investigate the crosstalk of airpollution 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 noveldrug target for prevention and treatment of SARS-CoV-2 infection. The proposal will leverageexpertise of our team on air pollution, respiratory diseases and an expert virologist with ongoing BSL-3SARS-CoV-2 research. Successful completion of this project will provide proof of concept for future studiesdirected towards development of a novel strategy of targeting host defense for prevention and treatment ofSARS-CoV-2 infection in susceptible populations.