ADAM-17 protease promotes inflammation and mortality while decreasing viral burden in a COVID-19 mouse model

Abstract

Abstract Angiotensin Converting Enzyme 2 (ACE2) is the primary cell entry receptor for SARS-CoV-1 and SARS-CoV-2 viruses. A disintegrin and metalloproteinase 17 (ADAM-17) is a protease located in the cell membrane of most cells that, upon cellular activation, cleaves ectodomains of transmembrane proteins, including that of ACE2, from cell surfaces. We hypothesized that blockade of ADAM-17 activity would alter COVID-19 pathogenesis. To assess this pathway, we blocked the function of ADAM-17 using a monoclonal antibody in the K18 human ACE2 Tg mouse model of COVID-19. Antibody-treated mice were healthier, less moribund, and had significantly less lung inflammation than saline treated mice. However, the viral burden in the lungs of anti-ADAM17 Ab-treated mice was significantly greater. ADAM17 also cleaves TNF-a and its blockade decreased lung TNF-a production induced by intratracheal LPS delivery. We are currently testing this possibility in the COVID-19 mouse model. Thus, ADAM-17 appears to have a critical anti-viral role, but also promotes damaging inflammation following SARS-CoV-2 infection. Since the inflammatory cascade is ultimately the reason for the adverse outcomes in COVID-19 patients, there may be a therapeutic application for the anti-ADAM-17 antibody.