Mechanism of pulmonary vascular wall thickening in COVID-19

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Principal Investigator: YUICHIRO Justin SUZUKI
Organization: GEORGETOWN UNIVERSITY
Fiscal Year: 2022
Award: $70,304
Funding agency: National Institute on Aging

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.

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