Mechanism of pulmonary vascular wall thickening in COVID-19

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Summary/Abstract Currently the world is suffering from the pandemics of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter host cells. So far, over five million people have been infected with SARS-CoV-2 and over 300,000 people have died of COVID-19 worldwide, causing serious health, economical, and sociological problems. The aging population with cardiovascular comorbidities is highly susceptible to be severely affected by and die of COVID-19. However, the mechanism underlying this increased susceptibility has not been defined. Lack of such knowledge interferes with the development of therapeutic strategies to prevent death by COVID-19. The long-term objective of our research is to define the pathogenic mechanism of the SARS-CoV-2 infection to identify new therapeutic targets to combat COVID-19. We recently identified the occurrence of pulmonary vascular wall thickening in patients infected with SARS-CoV-2 who died of COVID-19, but not in patients infected with SARS-CoV-1 or influenza virus. In this project, we will test the central hypothesis that the SARS-CoV-2 spike protein promotes cell growth signaling in lung vascular smooth muscle cells. This hypothesis is based on preliminary results obtained in my laboratory showing that (i) the treatment with recombinant SARS-CoV-2 spike protein (without the rest of viral components) strongly activates cell growth signaling (the activation of mitogen-activated protein kinase) in human pulmonary artery smooth muscle cells; (ii) the ACE2 receptor binding domain of SARS-CoV-2 spike protein alone is not sufficient to activate cell growth signaling; and (iii) SARS-CoV-2 spike protein increases the protein expression of ACE2. We plan to accomplish the objective by addressing the following specific aims: (1) Establish the uniformity of pulmonary vascular wall thickening in patients who died of COVID-19; (2) Determine the mechanism of SARS-CoV-2 spike protein-mediated cell signaling in pulmonary artery smooth muscle cells; and (3) Define the role of SARS-CoV-2 spike protein-mediated cell signaling in the COVID-19 pathology. This project is innovative because it will address a novel mechanism of the SARS-CoV-2 infection and pathogenesis and the role of pulmonary vasculatures in the pathology of COVID-19. Results of this project are significant because they are expected to contribute to the development of new therapeutic agents to reduce the death caused by COVID-19 that occurs largely in the aging population.