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Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients

Higher rates of serious illness and death from coronavirus SARS-CoV-2 (COVID-19) infection among older people and those who have comorbidities suggest that age- and disease-related biological processes make such individuals more sensitive to environmental stress factors including infectious agents like coronavirus SARS-CoV-2. Specifically, impaired redox homeostasis and associated oxidative stress appear to be important biological processes that may account for increased individual susceptibility to diverse environmental insults. The aim of this Viewpoint is to justify (1) the crucial roles of glutathione in determining individual responsiveness to COVID-19 infection and disease pathogenesis and (2) the feasibility of using glutathione as a means for the treatment and prevention of COVID-19 illness. The hypothesis that glutathione deficiency is the most plausible explanation for serious manifestation and death in COVID-19 patients was proposed on the basis of an exhaustive literature analysis and observations. The hypothesis unravels the mysteries of epidemiological data on the risk factors determining serious manifestations of COVID-19 infection and the high risk of death and opens real opportunities for effective treatment and prevention of the disease.

The novel coronavirus SARS-CoV-2 (COVID-19) continues to spread throughout the globe, affecting more and more people; thus, the identification of effective drugs for disease prevention and treatment is necessary. The overwhelming majority of people infected by SARS-CoV-2 have asymptomatic, mild, or moderate disease, and only 14% and 5% of patients developed severe or critical disease, respectively.1 Higher rates of serious illness and death from COVID-19 infection among older people and those who have comorbidities suggest that age- and disease-related biological processes make such individuals more sensitive to environmental stress factors including infectious agents like coronavirus SARS-CoV-2. Specifically, impaired redox homeostasis and associated oxidative stress appear to be important biological processes that may account for increased individual susceptibility to diverse environmental insults.

Oxidative stress is a nonspecific pathological condition reflecting an imbalance between the increased production of reactive oxygen species (ROS) and an inability of biological systems to detoxify the reactive intermediates or to repair the resulting damage.2 Notably, ROS are closely related with aging because they mediate a stress response to age-dependent damage.3 Mounting evidence supports the concept that oxidative stress and associated inflammation resulting from an increased production of ROS and/or decreased antioxidant defense contribute to the pathogenesis of various chronic diseases,4 including diabetes and cardiovascular and respiratory diseases, known to increase the risk of severe illness and death in COVID-19 patients.5 It is also known that virus-induced modulation of the host antioxidant response represents a crucial determinant for the progression of several viral diseases.6 In this regard, the antioxidant defense system protecting against oxidative stress is of great interest in the context of understanding the mechanisms underlying nonspecific sensitivity or resistance to infectious agents.

Glutathione (a tripeptide consisting of cysteine, glycine, and glutamate) is the most abundant molecular weight antioxidant that plays a crucial role in antioxidant defense against oxidative damage of cells from ROS and is also involved in the regulation of various metabolic pathways essential for whole body homeostasis.7 The maintenance of the highest (millimolar) concentrations of reduced glutathione (GSH) in most cell types highlights its vital and multifunctional roles in the control of various biological processes such as detoxification of foreign and endogenous compounds, protein folding, regeneration of vitamins C and E, maintenance of mitochondrial function, antiviral defense, regulation of cellular proliferation, apoptosis, and immune response.7 Despite a number of publications reporting beneficial effects of glutathione on human health, the key role of this powerful antioxidant in human physiology and pathology and in clinical applications still remains underestimated.

The aim of this Viewpoint is to justify (1) the crucial roles of glutathione in determining individual responsiveness to COVID-19 infection and disease pathogenesis and (2) the feasibility of using glutathione as a means for the treatment and prevention of COVID-19 illness.

ref: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263077/