Therapeutic Modulation of Virus‐Induced Oxidative Stress via the Nrf2‐Dependent Antioxidative Pathway

Abstract

Virus-induced oxidative stress plays a critical role in the viral life cycle as well as the pathogenesis of viral diseases. In response to reactive oxygen species (ROS) generation by a virus, a host cell activates an antioxidative defense system for its own protection. Particularly, a nuclear factor erythroid 2p45-related factor 2 (Nrf2) pathway works in a front-line for cytoprotection and detoxification. Recently, a series of studies suggested that a group of clinically relevant viruses have the capacity for positive and negative regulations of the Nrf2 pathway. This virus-induced modulation of the host antioxidative response turned out to be a crucial determinant for the progression of several viral diseases. In this review, virus-specific examples of positive and negative modulations of the Nrf2 pathway will be summarized first. Then a number of successful genetic and pharmacological manipulations of the Nrf2 pathway for suppression of the viral replication and the pathogenesis-associated oxidative damage will be discussed later. Understanding of the interplay between virus-induced oxidative stress and antioxidative host response will aid in the discovery of potential antiviral supplements for better management of viral diseases.

Progressive Rotavirus Infection Downregulates Redox-Sensitive Transcription Factor Nrf2 and Nrf2-Driven Transcription Units

“…Therefore, upregulation of the cytoprotective and detoxifying proteins seems to be beneficial not only for disruption of the ROS-dependent steps of viral life cycle but also for amelioration of the exacerbated conditions of infected host cells. In this regard, numerous pharmacological agents were shown to activate the Nrf2 pathway and lessen the burden of virus-induced oxidative stress [132]. The general consensus is that antioxidant therapy either by application of direct cellular antioxidants or through pharmacological upregulation of the cellular antioxidant defense is beneficial for hosts to combat against viral infection.…”

Molecular and Cellular Mechanisms for PRRSV Pathogenesis and Host Response to Infection

“…The JNK activation by PRRSV also contributes to virus-induced cytokine production (Lee and Lee, 2012;Liu et al, 2017b). Changes in redox balance during viral infection are linked to viral pathogenesis (Lee, 2018), and an oxidative stress is induced by PRRSV in both cells and pigs (Yan et al, , 2015. The increased ROS generation by PRRSV likely attributes to the elevated inducible nitric oxide synthase (iNOS), which is associated with the changes of heat shock protein 90 and caveolin-1 expression.…”

Roles of Nrf2 in Liver Diseases: Molecular, Pharmacological, and Epigenetic Aspects

“…In HCV-infected cells, Nrf2 activation is mediated through mitogen-activated protein kinases, casein kinase 2, phosphoinositide-3 kinase, and protein kinase C, thus contributing to cell survival against HCV infection [ 90 ]. In contrast, an inhibitory effect on the activation of Nrf2 and induction of ARE-dependent genes was reported, related to an increase of sMaf proteins [ 90 , 91 ]. In addition, the transcriptome analysis of HCV-replicating cells showed reduced expression of a variety of Nrf2-dependent genes [ 90 ].…”

“…Caffeic acid induces Nrf2 and HO-1 and inhibits HCV replication through induction of the IFNα antiviral response and p62-mediated Keap1/Nrf2 signaling [ 92 ]. Other compounds such as lucidone, andrographolide, aulforaphane, and celastrol were also shown to inhibit HCV replication through upregulating HO-1 via the Nrf2 pathway [ 91 ]. The controversial results on the Nrf2 activation status in HVC infection might be due to differences in experimental designs and conditions.…”