The Role of Glutathione in Prevention of COVID-19 Immunothrombosis: A Review

Abstract

Immunothrombosis has emerged as a dominant pathological process exacerbating morbidity and mortality in acute- and long-COVID-19 infections. The hypercoagulable state is due in part to immune system dysregulation, inflammation and endothelial cell damage, as well as a reduction in defense systems. One defense mechanism in particular is glutathione (GSH), a ubiquitously found antioxidant. Evidence suggests that reduction in GSH increases viral replication, pro-inflammatory cytokine release, and thrombosis, as well as decreases macrophage-mediated fibrin removal. The collection of adverse effects as a result of GSH depletion in states like COVID-19 suggest that GSH depletion is a dominant mechanism of immunothrombosis cascade. We aim to review the current literature on the influence of GSH on COVID-19 immunothrombosis pathogenesis, as well as the beneficial effects of GSH as a novel therapeutic for acute- and long-COVID-19.

Keywords: COVID-19; GSH; HIV; SARS-CoV-2; diabetes; glutathione; immunothrombosis; microclot; thrombosis.

Fig. 1.. Immunothrombosis induction.

(1) SARS-CoV-2 binds to ACE-2 receptor on type-2 pneumocyte cells. (2) Infection with SARS-CoV-2 results in recruitment of immune cells, including macrophages, which release cytokines. (3) Cytokines recruit more immune cells which produce excess cytokines, otherwise known as a cytokine storm. (4) The cytokine storm results in endothelial inflammation and damage, releasing tissue factor (TF) into circulation. (5) Cytokines recruit (a) monocytes, which release microparticles expressing intravascular TF, and (b) neutrophils, which release neutrophil extracytoplasmic traps (NETs). (6) The combination of TF and NETs activate immunothrombosis, generating clots and microclots. (7) Clotting and impaired blood flow results in impaired oxygen delivery and elevated D-dimer levels.

Fig. 2.. Role of GSH in COVID-19 Immunothrombosis.

(A) SARS-CoV-2 infection causes GSH deficiency, eventually leading to platelet activation and immunothrombi formation. (1) Initially, SARS-CoV-2 reduces GSH and increases GSSG. (2) reduction in GSH and increase in GSSG causes an increase in oxidative stress. (3) In turn, this elicits the release of pro-inflammatory cytokines IL-6 and TGF-β. (4) These cytokines suppress the enzymes iodothyronine deiodinases type I (D1) and type II (D2). (5) Reduced D1 and D2 impair glutamate cysteine ligase (GCL), the rate-limiting enzyme in the GSH synthesis pathway. (6) This results in a repeating cycle of depleted GSH and increased GSSG, causing (6a) increased platelet activation, and (6b) increased immunothrombi formation. (B) Supplementation with GSH increases GSH, resulting in decreased platelet activation and immunothrombi formation. (1) GSH supplement increases GSH and decreases GSSG. (2) The increase in GSH and decrease in GSSG reduce oxidative stress. (3) Reduced oxidative stress results in decreased IL-6 and TGF-β. (4) The increase in GSH and decrease in GSSG ultimately (4a) reduce platelet activation and (4b) immunothrombi formation.

Fig. 3.. The Role of GSH in COVID-19 Immunothrombosis.

Infection with SARS-CoV-2 results in decreased intracellular Cys and thiol due to decreased Cys uptake and increased thiol efflux, reducing GSH synthesis. Infection also inhibits Nrf2 and BRCA1, further reducing GSH synthesis. The reduction in GSH and increase in GSSG results in impaired ability to control oxidative stress. Increased oxidative stress further propagates the biochemical cascade by consuming additional GSH, increasing the production of cytokines IL-6 and TGF-β, as well as activating NF-κB. Increasing levels of IL-6 and TGF-β impair GCL, further reducing GSH synthesis. NF-κB increases the production of prothrombotic adhesion molecules which increase platelet activation. Increased GSSG and decreased GSH also contribute to further platelet activation. Together, these events lead to the increased production of immunothrombosis in COVID-19.