Abstract
Angiotensin Converting Enzyme 2 (ACE2) is the primary cell entry receptor for SARS-CoV and SARS-CoV-2 viruses. A disintegrin and metalloproteinase 17 (ADAM17) is a protease that cleaves ectodomains of transmembrane proteins, including that of ACE2 and the proinflammatory cytokine TNF-α, from cell surfaces upon cellular activation. We hypothesized that blockade of ADAM17 activity would alter COVID-19 pathogenesis. To assess this pathway, we blocked the function of ADAM17 using the monoclonal antibody MEDI3622 in the K18-hACE2 transgenic mouse model of COVID-19. Antibody-treated mice were healthier, less moribund, and had significantly lower lung pathology than saline-treated mice. However, the viral burden in the lungs of MEDI3622-treated mice was significantly increased. Thus, ADAM17 appears to have a critical anti-viral role, but also may promote inflammatory damage. Since the inflammatory cascade is ultimately the reason for adverse outcomes in COVID-19 patients, there may be a therapeutic application for the MEDI3622 antibody.
Keywords: ADAM19; COVID-19; SARS-CoV-2; inflammation; lung; mouse model; virus.
【저자키워드】 COVID-19, SARS-CoV-2, Inflammation, lung, mouse model, virus., ADAM19, 【초록키워드】 ACE2, antibody, SARS-CoV, monoclonal antibody, Proteins, protease, virus, adverse outcome, COVID-19 pathogenesis, mice, therapeutic, pathway, ADAM17, Critical, COVID-19 patients, TNF-α, K18-hACE2, Lung pathology, angiotensin, Inflammatory, Proinflammatory cytokine, SARS-CoV-2 viruses, transmembrane, blockade, ectodomain, viral burden, metalloproteinase, significantly lower, cellular activation, inflammatory cascade, Alter, Cell, Transgenic mouse, cell entry receptor, significantly increased, blocked, appear, less, promote, cleave, anti-viral role, lung;, 【제목키워드】 Model, mouse, burden, while, Increasing,