The role of oxidative stress in the pathogenesis of infections with coronaviruses

Abstract

Coronaviruses can cause serious respiratory tract infections and may also impact other end organs such as the central nervous system, the lung and the heart. The coronavirus disease 2019 (COVID-19) has had a devastating impact on humanity. Understanding the mechanisms that contribute to the pathogenesis of coronavirus infections, will set the foundation for development of new treatments to attenuate the impact of infections with coronaviruses on host cells and tissues. During infection of host cells, coronaviruses trigger an imbalance between increased production of reactive oxygen species (ROS) and reduced antioxidant host responses that leads to increased redox stress. Subsequently, increased redox stress contributes to reduced antiviral host responses and increased virus-induced inflammation and apoptosis that ultimately drive cell and tissue damage and end organ disease. However, there is limited understanding how different coronaviruses including SARS-CoV-2, manipulate cellular machinery that drives redox responses. This review aims to elucidate the redox mechanisms involved in the replication of coronaviruses and associated inflammation, apoptotic pathways, autoimmunity, vascular dysfunction and tissue damage that collectively contribute to multiorgan damage.

SARS-CoV-2 and the DNA damage response

“…Mitochondrial ROS regulates several pathways, which facilitate coronavirus replication in the cytoplasm. For example, it induces mitochondrial permeability transition pores, regulates endoplasmic reticulum stress and the unfolded protein response, and regulates mitophagy, which, in turn, contributes to coronavirus replication (reviewed in [161]). Most of these effects have been observed for SARS-CoV, but it seems reasonable to assume that similar effects would be observed with SARS-CoV-2.…”

“…SARS-CoV-2 can downregulate host cell antioxidant pathways, aiding replication. Specifically, it has been shown that NRF2induced genes, such as heme oxygenase 1 (HO-1) and NAD(P)H quinone oxydoreducatse 1 (NqO1), and superoxidase dismutase (SOD), are suppressed in SARS-CoV-2-infected cells and that the NRF2 pathway inhibits SARS-CoV-2 replication, in a way quite distinct from the host inflammatory response [161,167]. The viral Nsp14 protein interacts with the catalytic domain of the NAD-dependent deacetylase sirtuin 1 (SIRT1) and inhibits its ability to activate the NRF2/HMOX1 pathway [168].…”

“…The ACE2 receptor and its ligand have been shown to be important for the induction of redox stress. Ang II, the ACE2 ligand, activates NADPH oxidase, increasing ROS production [162]; this is offset by ACE2, which converts Ang II to angiotensin 1-7, causing a reduction in ROS [161,162]. Infection of cells with coronaviruses leads to reduced levels of ACE2 receptors and an increase in Ang II binding to ACE1, which causes an increase in ROS due to activation of NADPH oxidase [161,162].…”

“…Ang II, the ACE2 ligand, activates NADPH oxidase, increasing ROS production [162]; this is offset by ACE2, which converts Ang II to angiotensin 1-7, causing a reduction in ROS [161,162]. Infection of cells with coronaviruses leads to reduced levels of ACE2 receptors and an increase in Ang II binding to ACE1, which causes an increase in ROS due to activation of NADPH oxidase [161,162]. It has also been shown that S protein expression causes oxidative stress in endothelial cells, caused by activation of NOX2 [163].…”

“…Although there have been several large-scale studies examining the interactome for SARS-CoV-2 proteins, the results have tended to be somewhat contradictory (see above). However, components of different DDR pathways have been identified as binding partners for viral proteins, such as the association of POLD1 with Nsp7 and Nsp10 [158, 181], the association of MRE11 and RAD50 with Nsp14 [161], and the association of POLA1 and POLA2 with Nsp1 [158, 176–178, 180, 181]. Most of the reported interactions are summarized in .…”