Identification of SARS-CoV2-mediated suppression of NRF2 signaling reveals a potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate
cell biology drug discovery/repurposing immunology/immunity inflammation virology
Authors: Olagnier, David P. et al.
Link to paper: https://www.researchsquare.com/article/rs-31855/v1
Journal/ Pre-Print: Research Square
Tags: Cell Biology, Drug discovery/Drug repurpose, Immunology/Immunity, Inflammation, Virology
Figures so blurry impossible to interpret – therefore conclusions based solely on text.
1. The metabolite 4-octyl-itaconate (4-OI) induces an antiviral response mediated by NRF2.
2. NRF2 simultaneously inhibits SARS-CoV2 replication and proinflammatory cytokine release.
3. The FDA approved drug dimethyl fumarate inhibits SARS-COV2 replication and proinflammatory cytokine release. Therefore, it may show clinical benefit.
In response to oxidative stress the transcriptional factor NRF2 is activated inhibiting cell death pathways. The authors initially show NRF2s activation limits production of proinflammatory cytokines (e.g. IFN-B, TNFA and IL-1B) in response to viral challenge. Then unexpectedly find 4-octyl-itaconate (4-OI), an NRF2 agonist, inhibits replication of many viruses (SARS-CoV2, HSV1, Vaccinia and Zika virus). They find a pharmaceutically approved NRF2 agonist, dimethyl fumarate (DMF), inhibits both SARS-CoV2 replication and proinflammatory cytokine release. They suggest that DMF could be used therapeutically both to inhibit SARS-CoV2 replication and attenuate the proinflammatory cytokines thought to drive the pathology of the disease.
Impact for SARS-CoV2/COVID19 research efforts
Understand the immune response to SARS-CoV2/COVID19
Understand the virology and/or cell biology of SARS-CoV2/COVID19
Clinical symptoms and pathogenesis of SARS-Cov2/COVID19
Treat of SARS-CoV2/COVID19 positive individuals
(If data is as stated then dimethyl fumarate could be effectively repurpose to treat SARS-CoV2).
· In vitro study
· In vivo study (e.g. mouse, NHP)
Strengths and limitations of the paper
Novelty: In the field of innate immunity this a novel pathway by which cells can control overzealous innate immune activation while simultaneously fighting viral replication. In relation to SARS-CoV2 this paper identifies a drug potentially able to treat those already infected.
Standing in the field: The findings are broadly consistent with the current literature.
Appropriate statistics: Cannot see graphs properly but appropriate statistic seem to be in place from figure legends. Very low numbers of replicates.
Viral model used: SARS-CoV2 strain #291.3 FR-4286
Translatability: Yes, DMF is already in the clinic so potentially could be used to treat SARS-CoV2.
Main limitations: Figures are not visible so complete critical analysis of techniques used impossible. First, cancer cell lines have been used in this study; limited number of primary cells have been utilized. It would be important to know the role of DMF in physiological setting. Secondly, young patients are studied (below 58 years), as we know from literature NRF2 level goes down in aged population. Will DMF boost the NRF2 to optimum level in aged population? Thirdly, prior to clinical trials more in vitro primary cell data will be required.