Identification of SARS-CoV2-mediated suppression of NRF2 signaling reveals a potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

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 anti-oxidant 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 potent cellular anti-viral program, which potently inhibits replication of SARS-CoV2 across cell lines. The anti-viral program extended to inhibit 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, induction of NRF2 by 4-OI and DMF limited 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 suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2. One Sentence Summary: NRF2 agonists 4-octyl-itaconate (4-OI) and dimethyl fumarate inhibited SARS-CoV2 replication and virus-induced inflammatory responses, as well as replication of other human pathogenic viruses.

Immune-Boosting, Antioxidant and Anti-inflammatory Food Supplements Targeting Pathogenesis of COVID-19

“…The viral replication, in turn, triggers the activation of monocytes, macrophages, granulocytes resulting in the hyper inflammatory condition described as "cytokine storm" with the massive secretion of pro-inflammatory cytokines including interleukin (IL)-1, IL-6, IL-8, IL-12, tumor necrosis factor (TNF)-α, etc. This results in hyper inflammation of tissues and subsequent tissue fibrosis and pneumonia (4,7,10). Studies also indicate the involvement of oxidative stress in the pathogenesis of COVID-19.…”

“…In another study done on human HCoV-229E infection shows that deficiency in the expression of NRF-2 target, glucose-6-phosphate dehydrogenase (G6PDH) results in enhanced ROS as well as virus production (14). Incidentally, the NRF-2 levels were found to be suppressed in lung biopsies from COVID-19 subjects, on the other hand NRF-2 activators found to inhibit replication of SARS-CoV-2 and the inflammatory response (10). However, it is not known how SARS-CoV-2 infection causes suppression of NRF-2 signaling.…”

Can Activation of NRF2 Be a Strategy against COVID-19?

“…Given that changes in redox homeostasis in infected cells and lung inflammation are hallmarks of infections caused by respiratory viruses [ 70 ], the information obtained from viruses that affect the airways may be relevant for extrapolation to COVID-19. Indeed, experimental evidence is beginning to emerge, and it was recently demonstrated that the NRF2 activators dimethyl fumarate (DMF) and 4-octyl itaconate (4-OI), a cell-permeable analog of the endogenous anti-inflammatory metabolite itaconate [ 22 ], suppress the inflammatory response to SARS-CoV2 in human cells, including peripheral blood mononuclear cells (PBMCs) from COVID-19 patients [ 33 ].…”

Ionophore antibiotic X-206 is a potent inhibitor of SARS-CoV-2 infection in vitro

“…X-206 (12 nM) was effective at all time points with the most significant reduction in viral mRNA (measured 24 h after infection) observed at either 0.5 h pre-infection or 2h post-infection ( Figure 3 C). We also measured the TCID50/mL ( Olagnier et al, 2020 ) which demonstrated a nearly 2-fold log-reduction of infectious viral progeny in the supernatent at all time points ( Figure 3 D).

Figure 3 Comparison of polyether ionophores with cationic amphiphiles and time-dependence of the anti-viral activity of X-206.

…”