Investigating Effect of Air pollution and Host Defenses in SARS-CoV2 infection

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 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-CoV2 is emerging and airpollution; smoking and vaping have been associated with worst outcomes of SARS-CoV2 patients. There isa time sensitive urgent need to understand host defense mechanisms which are compromised due toenvironmental exposures and may increase susceptibility to SARS-CoV2 infection. This competing revisionwill forge collaboration with expert in SARS-CoV2 research to expand our horizon in this critical area. Wewill test the hypothesis of targeting a host defense pathway which is compromised in air pollution that mayprotect and modify the response to SARS-COV2 respiratory infection. Through the parent U grant, we havedemonstrated that chronic exposure to PM2.5 has an overarching role in epigenetic reprogramming. Ourstudies have established that transcription factor Nuclear factor erythroid-factor 2 (Nrf2) is a key activator ofanti-oxidative, anti-inflammatory, and innate immune defenses. We and others have demonstrated inhuman biospecimens and animal models that chronic exposure to PM2.5 causes a decline in Nrf2 activitythat correlates with compromised innate immune defenses. In mice deficient for Nrf2 (Nrf2-/-), viral andbacterial infection causes oxidative stress, worsened lung inflammation, acute lung injury and greatermortality compared to wildtype mice. Genetic or pharmacological activation of Nrf2 pathway can rescuethese effects. Disruption of Nrf2 pathway has been shown to cause upregulation of angiotensin-convertingenzyme 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 inimmunocompromised patients. The goal for this project is to investigate the crosstalk of air pollutionexposure, host defense and SARS-CoV2 infection. Preclinical testing of therapeutic efficacy of Nrf2activators will provide proof of concept for further development a novel drug target for prevention andtreatment 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. Successfulcompletion of this project will provide proof of concept for future studies directed towards development of anovel strategy of targeting host defense for prevention and treatment of SARS-CoV2 infection insusceptible populations.