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Review
. 2023 Dec 31;13(1):39.
doi: 10.3390/pathogens13010039.

The Role of the NRF2 Pathway in the Pathogenesis of Viral Respiratory Infections

Maria Daskou  1 , Leila Fotooh Abadi  2 , Chandrima Gain  1 , Michael Wong  1 , Eashan Sharma  1 , Arnaud John Kombe Kombe  2 , Ravikanth Nanduri  2 , Theodoros Kelesidis  1   2
Affiliations
Review

The Role of the NRF2 Pathway in the Pathogenesis of Viral Respiratory Infections

Maria Daskou et al. Pathogens. .

Abstract

In humans, acute and chronic respiratory infections caused by viruses are associated with considerable morbidity and mortality. Respiratory viruses infect airway epithelial cells and induce oxidative stress, yet the exact pathogenesis remains unclear. Oxidative stress activates the transcription factor NRF2, which plays a key role in alleviating redox-induced cellular injury. The transcriptional activation of NRF2 has been reported to affect both viral replication and associated inflammation pathways. There is complex bidirectional crosstalk between virus replication and the NRF2 pathway because virus replication directly or indirectly regulates NRF2 expression, and NRF2 activation can reversely hamper viral replication and viral spread across cells and tissues. In this review, we discuss the complex role of the NRF2 pathway in the regulation of the pathogenesis of the main respiratory viruses, including coronaviruses, influenza viruses, respiratory syncytial virus (RSV), and rhinoviruses. We also summarize the scientific evidence regarding the effects of the known NRF2 agonists that can be utilized to alter the NRF2 pathway.

Keywords: NRF2 pathway; inflammation; respiratory viruses; viral replication.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The nuclear factor erythroid 2-related factor 2 (NRF2) pathway regulates cellular responses to stress. (Left) Under resting (constitutive) condition, in the cytoplasm NRF2 is anchored with Kelch-like ECH-associated protein 1 (KEAP1). NRF2 binds KEAP1 and becomes ubiquinated, leading to degradation by the 26S proteasome. (Right) Under oxidative stress response, NRF2 escapes repression by KEAP1. The CUL3/KEAP1 complex that targets NRF2 for ubiquitination undergoes a change to a nonfunctional conformation. Thus, newly synthesized NRF2 is no longer ubiquitinated/degraded, rapidly accumulates, and translocates to the nucleus where it binds the small maf protein (sMaf) and antioxidant response element (ARE). Activation of ARE increases the expression of the antioxidant genes heme oxygenase 1 (HO-1), quinone oxidoreductase (NQO1), and glutathione (GSH), which blocks the progression of oxidative stress (OS). Thus, activation of the NRF2 pathway has cytoprotective effects and plays a key role in maintaining redox balance. Figure generated with Biorender (https://biorender.com/, accessed on 10 November 2023).
Figure 2
Figure 2
Cytoprotective effects of heme oxygenase 1 (HO-1), a key gene of the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, in viral infection. HO-1 is a metabolic enzyme that utilizes oxygen (O2), heme, and NADPH to catalyze the degradation of heme into carbon monoxide (CO), Fe2+, and biliverdin. HO-1 has antiviral properties through multiple pathways: (1) Free Fe2+ may act on viral replication by binding to the highly conserved divalent metal-binding pocket of the viral RNA and inhibiting enzymes that mediate viral replication. (2) Biliverdin may inhibit viral proteases. (3) Heterodimerization of HO-1 with interferon regulatory factor 3 (IRF3) facilitates the phosphorylation and nuclear translocation of IRF3 and the induction of type I interferon (IFN) gene expression that has antiviral properties. (4) CO activates protein kinase G (PKG), which inhibits NAPDH oxidases (NOX), preventing an increase in reactive oxygen species (ROS) and associated damage. (5) Biliverdin also has antioxidant properties, and it is converted by NRF2/ARE-regulated gene biliverdin reductase to the potent antioxidant bilirubin. Figure generated with Biorender (https://biorender.com/, accessed on 10 November 2023).
Figure 3
Figure 3
Bidirectional crosstalk between replication of respiratory viruses and NRF2. Depending on the phase of the infection (early versus late), the type of respiratory virus and the context of the redox responses, respiratory viruses can either activate (A) or inhibit (B) the NRF2 pathway and associated downstream genes such as HO-1, NQO1, and BCL2, which regulate ROS, inflammation, apoptosis, viral entry, and replication. Figure generated with Biorender (https://biorender.com/, accessed on 10 November 2023).
Figure 4
Figure 4
Crosstalk of SARS-CoV2 with the NRF2 pathway. The viral spike (S) protein binds to the receptor angiotensin-converting enzyme 2 (ACE2), leading to virion entry. The viral nucleocapsid is uncoated in the cytoplasm of the host cell and the viral positive-sense single-stranded RNA (+ssRNA) is translated and then cleaved into specific viral proteins. Autoproteolysis and co-translational cleavage of polypeptide to generate nsps is shown as (1)). (- Sense) subgenomic transcription and RNA replication is shown as (2). (+ Sense) subgenomic transcription and RNA replication is shown as (3). Translation of subgenomic mRNA into structural and accessory proteins is shown as (4). Viral RNA inside the host cell activates the DNA/RNA sensor cGAS, which signals through the adaptor STING. Host defense is conducted by double-stranded RNA-activated protein kinase R (PKR), which phosphorylates eIF2 and inhibits protein translation. PKR also phosphorylates p62, thus activating NRF2 upon removal of its repressor KEAP1 through autophagy. Inhibition of protein translation in turn activates the unfolded protein response (UPR). PERK, a crucial Ser/Thr protein kinase in UPR signaling, phosphorylates NRF2, resulting in its stabilization and increased transcriptional activity. Activation of the NRF2 pathway (i) represses IFN production by downregulating STING expression; and (ii) induces the expression of HO-1, generating Fe2+ that can bind to the divalent metal-binding pocket of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV2 and inhibit its catalytic activity. Thus, the NRF2 pathway is involved in multiple pathways involved in SARS-CoV-2 pathogenesis. Abbreviations: ACE2, angiotensin-converting enzyme 2; eIF2, eukaryotic initiation factor 2; ER, endoplasmic reticulum; ERGIC, ER–Golgi intermediate compartment; HO-1, heme oxygenase 1; IFN, interferon; KEAP1, Kelch-like ECH-associated protein 1; NRF2, nuclear factor erythroid 2 p45-related factor 2; PERK, PKR-like endoplasmic reticulum kinase; P, phosphorylation; PKR, protein kinase R; STING, stimulator of interferon genes. Figure generated with Biorender (https://biorender.com/, accessed on 10 November 2023).
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