Regulation of the SARS-CoV-2 receptor ACE2 by ADAM17

Illustration of IL-6 receptor

The spike (S) protein expressed by SARS-CoV (2002/2003 SARS pandemic) and SARS-CoV-2 (COVID-19) recognize the receptor ACE2 on human cells. Acute respiratory distress syndrome (ARDS) is a main cause of death of COVID-19 in vulnerable individuals.

One of the main mechanisms for ARDS is the development of a cytokine storm, including high levels of IL-6 and TNF-alpha. ACE2 can be clipped from the surface of cells by proteases including ADAM17, and this appears to increase viral infection. ADAM17 also mediates the release of TNF-alpha and IL-6 receptor.

“The Walcheck lab has extensive experience and resources to study and block ADAM17 function. For this pilot study, we will use recombinant SARS-CoV-2 spike protein and SARS-CoV-2 pseudoviruses for ACE2 engagement. We anticipate that ADAM17 inhibition will reduce ACE2 clipping and viral entry as well as cytokine production. If successful, the pilot study will be leveraged for drug development to target ADAM17 and federal funding for further research,” said Bruce Walcheck, PhD, professor of Veterinary and Biomedical Sciences.

Project collaborators include Fang Li, PhD, and Jianming (Jimmy) Wu, DVM, PhD.

This project is supported by the UMN Campus Public Health Officer's CO:VID (Collaborative Outcomes: Visionary Innovation & Discovery) grants program, which support University of Minnesota faculty to catalyze and energize small-scale research projects designed to address and mitigate the COVID-19 virus and its associated risks.