The role of short ACE2 in Sars-CoV-2 infection and patients susceptibility to COVID-19
Lead Research Organisation:
University of Southampton
Department Name: Clinical and Experimental Sciences
Abstract
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.
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.
Organisations
Publications
Dalbay M, Humbert V, Spalluto M
(2022)
Investigating roles of SARS-CoV-2 receptor ACE2 isoforms, in SARS-CoV-2 infection in the airway epithelium
Mennella V
(2023)
Encyclopedia of Cell Biology
Mennella V
(2022)
Nanometer-Scale Molecular Mapping by Super-resolution Fluorescence Microscopy.
in Methods in molecular biology (Clifton, N.J.)
Spalluto MC, Humbert MV, Dalbay M
(2023)
The role of SARS-CoV-2 receptor ACE-2 isoforms in SARS-CoV-2 infection in the airway epithelium.
Description | 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. 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. |
Exploitation Route | It is 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. |
Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
URL | https://www.sciencedaily.com/releases/2021/01/210111112135.htm |
Description | The Mechanisms of Airway Defence |
Amount | £511,831 (GBP) |
Funding ID | MC_UU_00025/13 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 06/2021 |
Description | Invited oral presentation of a team member |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | A member of the team (Dr Melis Dalbay) presented the work on ACE2 at the "advanced imaging in life sciences workshop" Koc University in Instanbul |
Year(s) Of Engagement Activity | 2023 |
URL | https://twitter.com/CytoLabKoc/status/1599723223377072132 |
Description | Keynote lecture at Koc University for the "advanced imaging in life sciences workshop" |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | We presented our work at the "Advanced Imaging in Life Sciences" workshop at Koc University in Instanbul supported by EMBO Young Investigator Program. As part of the two days workshop, we trained groups of Ph.D. students and postdocs in Super-resolution imaging data collection. We have engaged with local politicians to promote the imaging ecosystem in EU-underfunded countries. |
Year(s) Of Engagement Activity | 2023 |
URL | https://twitter.com/CytoLabKoc/status/1599723223377072132 |