Targeting the mitochondria in COVID‑19 pneumonia: The cardiopulmonary effects of a SARS-CoV-2 mitochondriopathy

Archer, Stephen L | $422,280

Ontario Queen's University 2021 CIHR 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.

With funding from the Government of Canada

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