Grant: Operating Grant: COVID-19 - Project Grant

COVID-19 is an acute respiratory illness caused by SARS-CoV-2. COVID-19 has caused > 223 million infections and >4.1 million deaths. Most infected people are mildly symptomatic; however, ~5% suffer respiratory failure requiring hospitalization and 1.5% die, usually of hypoxia (low blood oxygen) and lung injury. While vaccines offer hope, mutant viruses may evade vaccine protection and 20% of the population remain vaccine hesitant. COVID-19 is the third coronavirus to emerge in 20 years; and yet we lack understanding of coronavirus pneumonia or curative therapies. In 2020, we discovered that SARS-CoV-2 may worsen COVID-19 pneumonia by targeting mitochondria in airway epithelial cells (AEC) and pulmonary artery smooth muscle cells (PASMC). Mitochondria are not just the powerhouse of the cell; they also control programmed cell death (apoptosis) and regulate hypoxia (hypoxic pulmonary vasoconstriction; HPV). SARS-CoV-2 damages mitochondria causing excessive AEC apoptosis and inhibiting HPV which worsens lung injury and hypoxemia. Our team has expertise in mitochondrial biology, SARS-CoV-2, virology, transcriptomics, synthetic chemistry, molecular imaging and disease pathogenesis. As part of a new collaboration with a SARS-CoV-2 expert at the Vaccine and Infectious Disease Organization (VIDO), we are testing the impact of replicating SARS-CoV-2 on mitochondria (structure/function/gene expression) in lung cells and assessing the effects of novel drugs that could treat COVID-19 mitochondriopathy in a SARS-CoV-2 hamster model. We also study conserved mechanisms of coronavirus cardiopulmonary toxicity using human (HCoV-OC43) and mouse (MHV-1) coronaviruses. Our in-silico drug discovery pipeline has identified new apoptosis inhibitors which, along with drugs repurposed to enhance HPV, we will test in two preclinical COVID-19 models. This research will identify the role of mitochondria in coronavirus pneumonia and create mitochondria-targeted therapies for COVID-19.