The role of short ACE2 in Sars-CoV-2 infection and patients susceptibility to COVID-19

The virus responsible for COVID-19, SARS-CoV-2 utilizes a protein on the surface of cells named Angiotensin Converting Enzyme II (ACE2) as an entry gate. The presence and amount of ACE2 on specific cells is largely responsible for the ability of the SARS-CoV-2 virus to infect cells in the human body. It is therefore of critical importance to study how ACE2 levels vary in different cells and individuals, especially in categories at risk for COVID-19, to understand how this could affect their predisposition to infection and disease severity.

We recently discovered that airway cells express a second form of ACE2, which we named short ACE2, in addition to the previously known, long form of ACE2. This novel short ACE2 does not appear to allow virus entry because it lacks regions involved in virus interaction. Surprisingly, we also discovered that short ACE2 is the main form produced in response to Interferons (IFNs); molecules released from cells of the immune system in response to viral infections to protect our tissues.
These discoveries made clear that there is an urgent need to better understand the pattern of long and short ACE2 expression in cells and how this varies in patients. Since short ACE2 is IFNs-regulated, and it is not competent for SARS-CoV-2 entry, we reason that it might be part of a mechanism for protecting airway cells from SARS-CoV-2 infection.

In this proposal we will study the levels of short and long ACE2 in different cells and patients to correctly understand the relationship between ACE2 levels and susceptibility to infection from SARS-CoV-2. In particular, we will study patients at particular risk of infection to COVID-19 such as Black, Asian and Minority Ethnic (BAME) patients, and patients with severe respiratory diseases such as COPD. To better understand the function of short ACE2 and its potential role in protecting cells from viral infection, we will generate cellular models including human airway cells lacking or having an excess of short ACE2 to investigate its effect on SARS-CoV-2 infection.

This study will generate critical information about the interaction between the virus and different cell types in the lung. Importantly it will help identify why some people are more susceptible to SARS-CoV-2 and offer insight into novel therapeutic possibilities targeting short ACE-2; ones aimed at reducing viral transmission and COVID-19 disease severity.