ABSTRACT
The transcription factor NRF2 is central to redox homeostasis in animal cells and is a well-known driver of chemoresistance in many types of cancer. Recently, new roles have been ascribed to NRF2 which include regulation of antiviral interferon responses and inflammation. In addition, NRF2 is emerging as an important factor in antiviral immunity through interferon-independent mechanisms. In the review, we give an overview of the scientific progress on the involvement and importance of NRF2 in the context of viral infection.
ABSTRACT
Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here, we demonstrate that the NRF2 antioxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular antiviral program that potently inhibits replication of SARS-CoV2 across cell lines. The inhibitory effect of 4-OI and DMF extends to the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, 4-OI and DMF limit host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and in suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Dimethyl Fumarate/agonists , NF-E2-Related Factor 2/metabolism , Pneumonia, Viral/drug therapy , Succinates/agonists , Adult , Antioxidants/pharmacology , Betacoronavirus/metabolism , COVID-19 , Coronavirus Infections/virology , Dimethyl Fumarate/pharmacology , Female , Gene Expression , Gene Knockdown Techniques , Humans , Interferon Type I , Lung/pathology , Male , NF-E2-Related Factor 2/genetics , Pandemics , Pneumonia, Viral/virology , SARS-CoV-2 , Signal Transduction/drug effects , Succinates/pharmacology , Virus Replication/drug effectsABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
