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The Antioxidant Pathway: A Potential Target for Treating COVID-19

Study of the KEAP1/NRF21 antioxidant pathway to curb replication of the virus and the inflammation associated with infection, and search for a preventive treatment

The condition of patients severely affected by the SARS-CoV-22 virus can often deteriorate to a fatal degree due to a runaway response by the immune system, known as a cytokine storm. The goal of Paul-Henri ROMEO, Director of the Institute of Cellular and Molecular Radiobiology, and the partner teams is to identify the predictive biomarkers of the cytokine storm and to find a preventive therapy based on already-approved molecules. Their approach? The KEAP1/NRF2 antioxidant pathway.

Project Identity

Project Initiator: CEA Paris / François-Jacob Institute of Biology Year(s) of Support: 2020-2021
Support Provided: Analyses, reagents Amount Provided: 200,000 euros
Location: CEA, Fontenay-aux-Roses, France

Air Liquide Monitor:

Géraldine Farjot, Air Liquide Santé International

 

The Role of the KEAP1/NRF2 Antioxidant Pathway

The hypothesis of Paul-Henri Roméo's team and the partner teams is that the activation of the body’s protection mechanisms against oxidative stress can help the body fight the SARS-CoV-2 virus and limit viral replication. Indeed, the body develops defenses against inhaled oxidants to protect the lungs. The KEAP1/NRF2 antioxidant pathway, activated by these oxidants, makes a major contribution to this protection by enabling the expression of antioxidant proteins.

The goal of the research work is therefore to demonstrate the relevance of targeting the KEAP1/NRF2 antioxidant pathway for treating COVID-19.
The results of the work could have applications in combating SARS-CoV-2, but also other respiratory diseases involving a cytokine storm.

How It Works

How It Works – The research program will take place in several phases:

  • Study of the expression of the Trim33 gene necessary for the inflammatory response.
  • Results obtained by studying patients suffering from asthma or COPD indicate that the level of expression of the Trim33 gene in blood cells could be a biomarker for aggravation of the disease. Trim33 gene expression analyses will be performed on COVID-19 patients to determine whether the level of expression of Trim33 is a predictor of how the disease will develop.
  • Similar study but targeting the KEAP1/NRF2 pathway.
  • Analysis of blood cells at different stages of the disease in order to map and identify potential biomarkers. 
  • Validation of biomarkers using the data from the CORIMUNO-19 therapeutic trial conducted by the AP-HP (Paris region university hospital trust) on a cohort of 800 patients suffering from COVID-19.
  • Study of the drugs currently being tested as part of the CORIMUNO-19 clinical trial: do they have a positive impact on the expression of the cytokines responsible for inflammation and do they use the KEAP1/NRF2 pathway? The studies will be extended to the effects of direct activators of the KEAP1/NRF2 pathway on the evolution of viral replication and on the cytokine storm.

Multidisciplinary Research Teams

The research project is conducted jointly by several research teams: 

  • The team led by Paul-Henri ROMEO, Director of the Institute of Cellular and Molecular Radiobiology,
  • Teams from the IDMIT institute (Infectious Diseases Models for Innovative Therapies) at the François Jacob Institute of Biology (CEA Fundamental Research Department)
  • The Rhumatology team of Inserm joint research unit UMR1184 at the Hôpital Bicêtre.