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

Jodi F. Hedges, Deann T. Snyder, Amanda Robison, Heather M. Grifka-Walk, Karlin Blackwell, Kelly Shepardson, Douglas Kominsky, Agnieszka Rynda-Apple, Bruce Walcheck, Mark A. Jutila

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article number918881
JournalFrontiers in immunology
Volume13
DOIs
StatePublished - Jun 10 2022

Bibliographical note

Funding Information:
This work was supported by funding from the MSU Vice-President for Research, Economic Development and Graduate Education office, MSU College of Agriculture and Department of Microbiology and Cell Biology, and USDA/NIFA Multi-State and Hatch Funds.

Publisher Copyright:
Copyright © 2022 Hedges, Snyder, Robison, Grifka-Walk, Blackwell, Shepardson, Kominsky, Rynda-Apple, Walcheck and Jutila.

Keywords

  • ADAM19
  • COVID-19
  • SARS-CoV-2
  • inflammation
  • lung
  • mouse model
  • virus

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