An ADAM17-Neutralizing Antibody Reduces Inflammation and Mortality While Increasing Viral Burden in a COVID-19 Mouse Model

Frontiers in Immunology

Amanda Robison¹  Douglas Kominsky¹  Mark A. Jutila¹  Jodi F. Hedges¹  Kelly Shepardson¹  Karlin Blackwell¹  Deann T. Snyder¹  Heather M. Grifka-Walk¹  Agnieszka Rynda-Apple¹  Bruce Walcheck² 

[1] Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT, United States;Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN, United States;

关键词: ADAM19;    COVID-19;    SARS-CoV-2;    lung;    inflammation;    virus;   

DOI  :  10.3389/fimmu.2022.918881

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown