How Aging and Oxidative Stress Influence the Cytopathic and Inflammatory Effects of SARS-CoV-2 Infection: The Role of Cellular Glutathione and Cysteine Metabolism

Abstract

SARS-CoV-2 infection can cause a severe respiratory distress syndrome with inflammatory and thrombotic complications, the severity of which increases with patients’ age and presence of comorbidity. The reasons for an age-dependent increase in the risk of severe COVID-19 could be many. These include defects in the homeostatic processes that control the cellular redox and its pivotal role in sustaining the immuno-inflammatory response to the host and the protection against oxidative stress and tissue degeneration. Pathogens may take advantage of such age-dependent abnormalities. Alterations of the thiol redox balance in the lung tissue and lining fluids may influence the risk of infection, and the host capability to respond to pathogens and to avoid severe complications. SARS-CoV-2, likewise other viruses, such as HIV, influenza, and HSV, benefits in its replication cycle of pro-oxidant conditions that the same viral infection seems to induce in the host cell with mechanisms that remain poorly understood. We recently demonstrated that the pro-oxidant effects of SARS-CoV-2 infection are associated with changes in the cellular metabolism and transmembrane fluxes of Cys and GSH. These appear to be the consequence of an increased use of Cys in viral protein synthesis and to ER stress pathway activation that interfere with transcription factors, as Nrf2 and NFkB, important to coordinate the metabolism of GSH with other aspects of the stress response and with the pro-inflammatory effects of this virus in the host cell. This narrative review article describes these cellular and molecular aspects of SARS-CoV-2 infection, and the role that antivirals and cytoprotective agents such as N-acetyl cysteine may have to limit the cytopathic effects of this virus and to recover tissue homeostasis after infection.

Intrahepatic Fat Content and COVID-19 Lockdown in Adults with NAFLD and Metabolic Syndrome

“…NAFLD is related to increased oxidative stress, even in early stages of the disease [ 39 ]. On the other hand, oxidative stress is a risk factor for COVID-19 infection [ 40 ]. However, some authors have shown that oxidative stress was reduced due to confinement, as exposure to urban pollutants was reduced [ 41 ].…”

Antioxidant, Anti-inflammatory, and Immunomodulatory Roles of Nonvitamin Antioxidants in Anti-SARS-CoV-2 Therapy

“…Perturbations of the thiol–disulfide redox balance in the lung tissue and lining fluids promotes the risk of infection and lowers the host’s ability to react to pathogens and hamper complications. 365 …”

“… 66 In the context of viral pathology, mainly during the first stages, there is an increased cysteine uptake to sustain viral replication, while the enhanced viral protein synthesis leads to thiol depletion and oxidative stress activation. 365 The corresponding oxidized form, cysteine disulfide, at concentrations higher than 300 μM in the elderly, is associated with an increased cardiovascular risk, 373 a condition tightly linked to COVID-19 severity. Benefits imparted by GlyNAC supplementation encompass: amelioration of glutathione deficiency, of glycine and cysteine profile, control on oxidative stress and inflammation, and correction of mitochondrial, endothelial vascular dysfunction, and insulin resistance, as proved in human clinical trials.…”

“…It is considered that these represent the repercussions of an enhanced cysteine utilization in viral protein synthesis and endoplasmic reticulum stress activation that impacts the expressions of both Nrf2 and NF-kB, transcription factors responsible for the modulation of oxidative stress and glutathione metabolism, with relevance for the control of the pro-inflammatory impact of the virus. Perturbations of the thiol–disulfide redox balance in the lung tissue and lining fluids promotes the risk of infection and lowers the host’s ability to react to pathogens and hamper complications …”

“…A pilot study focused on GlyNAC supplementation in patients hospitalized for acute COVID-19 infection, and having high oxidative stress and impaired glutathione levels proved that cysteine (from N -acetylcysteine) supports mitochondrial metabolism and is a sulfhydryl group donor, required for maintaining redox homeostasis and for biosynthesis of various metabolites . In the context of viral pathology, mainly during the first stages, there is an increased cysteine uptake to sustain viral replication, while the enhanced viral protein synthesis leads to thiol depletion and oxidative stress activation . The corresponding oxidized form, cysteine disulfide, at concentrations higher than 300 μM in the elderly, is associated with an increased cardiovascular risk, a condition tightly linked to COVID-19 severity.…”