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. Viral infections usually cause disease through direct cytopathogenic effects and excessive inflammatory responses. Here, Olagnier et al. show that two NRF2 agonists, 4-OI and DMF, possess broad IFN-independent antiviral activity and decrease host inflammatory response to SARS-CoV-2 infection.
【저자키워드】 immunology, SARS-CoV-2, Microbiology, 【초록키워드】 COVID-19, SARS-CoV2, Gene Expression, Inflammatory responses, Antiviral, SARS-COV-2 infection, Infection, antiviral activity, virus, antioxidant, coronavirus 2, SARS-CoV2 infection, Nrf2, type I interferon, airway, Replication, pathway, virus replication, cytopathogenic effect, respiratory, disease, mechanism, COVID-19 patients, cellular, cell lines, biopsy, fumarate, Zika virus, pathogenic viruses, inhibitory effect, pathogenic, pro-inflammatory response, agonist, host inflammatory response, COVID-19 pathology, vaccinia, pathogenic virus, effective, limit, consequence, decrease, agonists, addition, clinically, inhibit, required, approved, induce, suppressed, Herpe, 【제목키워드】 Antiviral, anti-inflammatory activity, fumarate, reveal,