Targeting the Master Regulator of Cellular Redox Homeostasis, Nrf2, in SARS-CoV-2 Infection

An extensive body of literature supports a protective role of the transcription factor, Nrf2, against viral susceptibility and replication, including to respiratory viruses such as influenzae and respiratory syncytial virus (RSV). Nrf2 has been described as the “guardian of healthspan”, as it regulates large gene networks that control redox balance, cellular defense and “survival” genes and a number of studies have implicated Nrf2 as a regulator of susceptibility to respiratory viral infections. Since viruses need to keep oxidative stress at a level optimal for viral reproduction, which is higher than normal, but not be so high as to kill the host cell, viruses have evolved mechanisms for manipulating the Nrf2 pathway in both directions, depending on the viral needs. This also suggests that we should be able to manipulate Nrf2 activity therapeutically to fend off viral infections. Maximal infection with SARS-CoV-2, the virus responsible for COVID-19, depends on host cell factors ACE2 and TMPRSS2. The viral spike protein (S) initiates viral attachment to target cells via binding of the S protein to the cellular receptor, ACE2. Viral attachment is followed by S protein “priming” via the cellular protease TMPRSS2, which cleaves S protein and allows fusion of viral and cellular membranes. The priming event can be blocked by a clinical inhibitor of the TMPRSS2 protease, camostat mesylate, but also by the human anti-protease Plasminogen Activator Inhibitor-1 (PAI-1), encoded by the SERPINE1 gene. Acetylation of Nrf2 increases binding to cognate response elements (ARE) in target gene promoters and increases Nrf2-dependent transcription. We have found that Nrf2-activation downregulates TMPRSS2 and upregulates SERPINE1, suggesting that this could protect cells from SARS-CoV-2 infection. Additionally, Nrf2-activation downregulated histone deacetylase 5 (HDAC5), the isozyme responsible for deacetylation and attenuation of Nrf2. Thus, PB125 might also protect cells from viral infection by mitigating the deacetylation of Nrf2. Furthermore, in stimulated primary human pulmonary artery endothelial cells, Nrf2 activation resulted in marked downregulation of cytokines genes, including IL-1-beta, IL-6, TNF-alpha, the cell adhesion molecules ICAM-1,VCAM-1, and E-selectin, and a group of IFN-gamma-induced genes. Many of these are components of the “cytokine storm” observed in fatal cases of COVID-19, suggesting that Nrf2 activation may significantly decrease the intensity of the storm. Thus, Nrf-2 activation may protect COVID-19 patients by targeting a number of steps along the course of pathogenesis.