Glutathione deficiency in the pathogenesis of SARS-CoV-2 infection and its effects upon the host immune response in severe COVID-19 disease Original paper

What was reviewed?

This review examined how glutathione deficiency contributes to the pathogenesis of SARS-CoV-2 infection and worsens immune dysfunction in severe COVID-19 disease. The authors focused on the role of oxidative stress, excessive reactive oxygen species production, and impaired redox balance during viral infection. The paper analyzed how reduced intracellular glutathione levels disrupt immune signaling, increase inflammation, and promote tissue damage. It also reviewed molecular pathways such as NADPH oxidase activation, NF-κB signaling, and Nrf2 dysregulation that link glutathione depletion to cytokine storm, endothelial injury, and acute respiratory distress syndrome. The review framed glutathione as a central regulator of immune resilience rather than only an antioxidant molecule.

Who was reviewed?

The authors reviewed evidence from human clinical studies, experimental models, and mechanistic research involving patients with COVID-19 and populations at high risk for severe disease. These included older adults and individuals with diabetes, cardiovascular disease, hypertension, obesity, and chronic lung disease. The review also considered immune cells relevant to COVID-19 pathology, including neutrophils, macrophages, endothelial cells, and lymphocytes. No single patient cohort was analyzed. Instead, the authors synthesized findings across multiple studies that examined immune and redox alterations during SARS-CoV-2 infection.

Most important findings

The review showed that low glutathione levels represent a shared biological vulnerability across all major COVID-19 risk factors. SARS-CoV-2 infection rapidly increases reactive oxygen species through NADPH oxidase activation, mitochondrial dysfunction, and inflammatory signaling. This oxidative burden consumes intracellular glutathione and weakens antioxidant defenses. Glutathione depletion amplifies NF-κB activation, promotes cytokine release, and enhances neutrophil extracellular trap formation. The authors highlighted how reduced glutathione impairs T-cell proliferation, promotes lymphocyte apoptosis, and drives immune exhaustion. Low glutathione also increases viral entry by strengthening spike protein binding to ACE2 and worsens endothelial dysfunction, thrombosis, and lung injury.

Key implications

This review positions glutathione deficiency as a modifiable driver of COVID-19 severity rather than a secondary consequence of infection. Restoring glutathione homeostasis may reduce oxidative damage, dampen hyperinflammation, and improve immune competence during viral illness. The findings support early interventions that enhance intracellular glutathione levels through precursor availability or redox pathway support. Clinicians should consider redox imbalance as a core contributor to immune failure, tissue injury, and mortality in severe COVID-19 disease, especially in high-risk patients.