SARS-CoV-2 infection and oxidative stress: Pathophysiological insight into thrombosis and therapeutic opportunities

Abstract

The current coronavirus disease 2019 (COVID-19) pandemic has presented unprecedented challenges to global health. Although the majority of COVID-19 patients exhibit mild-to-no symptoms, many patients develop severe disease and need immediate hospitalization, with most severe infections associated with a dysregulated immune response attributed to a cytokine storm. Epidemiological studies suggest that overall COVID-19 severity and morbidity correlate with underlying comorbidities, including diabetes, obesity, cardiovascular diseases, and immunosuppressive conditions. Patients with such comorbidities exhibit elevated levels of reactive oxygen species (ROS) and oxidative stress caused by an increased accumulation of angiotensin II and by activation of the NADPH oxidase pathway. Moreover, accumulating evidence suggests that oxidative stress coupled with the cytokine storm contribute to COVID-19 pathogenesis and immunopathogenesis by causing endotheliitis and endothelial cell dysfunction and by activating the blood clotting cascade that results in blood coagulation and microvascular thrombosis. In this review, we survey the mechanisms of how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces oxidative stress and the consequences of this stress on patient health. We further shed light on aspects of the host immunity that are crucial to prevent the disease during the early phase of infection. A better understanding of the disease pathophysiology as well as preventive measures aimed at lowering ROS levels may pave the way to mitigate SARS-CoV-2-induced complications and decrease mortality.

Keywords: COVID-19; Oxidative stress; Pathophysiology; SARS-CoV-2; Thrombosis.

Graphical abstract

Fig. 1

Immunopathology of COVID-19. (A) Pathway by which SARS-CoV-2 induces expression of cytokines, chemokines, and interferons. SARS-CoV-2 binds to host ACE2 and TMPRSS2 to gain entry into cells and then releases its RNA to the cytoplasm. This RNA is then recognized by the innate immune pathway via PAMP receptors including RIG-I and MDA-5, which then bind to MAVS that activates NF-κB through a signalling cascade involving E3 ubiquitin kinases. Activated NF-κB can then translocate into the nucleus, where it induces transcription of pro-inflammatory cytokines and chemokines. The E3 ubiquitin kinases and ligands also phosphorylate IRF3 and IRF7, which enter the nucleus to initiate transcription of IFN I. (B) Mechanisms of evasion of the innate immune response by SARS-CoV-2. Although IFNs play a key role in the initiation of the innate immune response, SARS-CoV-2 induces delayed IFN I secretion, particularly in older patients and those with comorbidities, which reduces chemotaxis resulting in a weaker innate immune response. This weakened response allows enhanced viral replication, which results in hyper-activation of Th1 cells that, in turn, activate macrophages by releasing IFN-γ. This activation leads to the production and secretion of IL1, IL6, IL8, and TGF-β, the latter of which activates Th17 cells to secrete IL17, which, collectively, produces the cytokine storm.

Fig. 2

SARS-CoV-2 and ROS. (A) In general, ROS (primarily, O₂^{• −}, H₂O₂, and ^•OH) is generated via a cascade of reactions initiated by the production of O₂^{• −} inside cells that involve endogenous (e.g. NADPH oxidase, myeloperoxidase, and electron transport-mitochondria) and exogenous (inflammation, radiation, chemicals, and drugs) cellular sources. (B) SARS-CoV-2 infection decreases levels of SOD, GSH and GPx, and increases levels of NADPH oxidase enzymes, which could increase oxidative stress.

Fig. 3

Potential mechanism by which SARS-CoV-2 infection increases oxidative stress. SARS-CoV-2 inactivates the ability of ACE2 to convert Ang II to Ang 1–7 which promotes the production of O₂^{• −}. Moreover, SARS-CoV-2 infection directly increases the production of O₂^{• −} and other ^•OH radicals via an increase of the neutrophils/lymphocytes ratio through the NADPH oxidase pathway.

Fig. 4

Potential mechanisms of SARS-CoV-2-induced vascular thrombosis. SARS-CoV-2 infects endothelial cells (EC) through ACE2 mediated entry. This may lead to a downregulation of ACE2, increasing Ang II levels, which increases oxidative stress. Moreover, SARS-CoV-2 stimulates polymorphonuclear cells (mostly neutrophils) that also enhances ROS generation through their NADPH oxidase pathway. In severe cases of COVID-19, activated macrophages contribute to a cytokine storm by releasing various cytokines (e.g. IL-6 and TNFα). The oxidative stress and cytokine storm induce EC dysfunction and inflammation (endotheliitis) that is characterized by EC swelling and apoptosis. Endotheliitis activates the blood clotting cascade, factors V and VIII, and elicits vWF from Weibel-palade bodies found in endothelial cells. In addition, elevated levels of CRP and D-dimers also promote hypercoagulability. The cytokine storm activates platelets which then interact with neutrophils, inducing the formation of the neutrophil extracellular trap (NET). The NET stimulates thrombin production and fibrin deposition which lead to vascular (microvascular and macrovascular) thrombosis. The thrombus may break down into smaller emboli and then travel downstream into smaller blood vessels, where they can become occluded and cause necrosis and ischemia of the tissue.

Fig. 5

The Keap1/Nrf2 signalling pathway involved in antioxidant production. In healthy conditions, Nrf2 is constantly ubiquitinated (Ub) by Keap1 in the cytoplasm and subsequently degraded by the proteasome. In presence of ROS or electrophiles, Keap1 is inactivated, leading to the accumulation of Nrf2 in the cytosol and subsequent translocation to the nucleus where it stimulates transcription of many target genes with antioxidant response elements (ARE) sequences in their promoters.

Fig. 6

Antioxidant mechanism of itaconate and its derivatives. Itaconate and its derivatives decrease ROS levels via SDH inhibition and induction of the antioxidant response via activation of the Nrf2 signalling pathway. Moreover, they also increase the expression of activating transcription factor-3 (ATF3) and the ATF3-driven stress response in macrophages to diminish pro-inflammatory cytokine gene expression and mitochondrial stress.

Fig. 7

Possible pharmacological targets of NAC in patients with COVID-19.