Content uploaded by Alexey V Polonikov
Author content
All content in this area was uploaded by Alexey V Polonikov on May 13, 2020
Content may be subject to copyright.
Endogenous deficiency of glutathione as the most likely cause of serious manifestations and death
1
from novel coronavirus infection (COVID-19): a hypothesis based on literature data
2
and own observations
3
Alexey V. Polonikov, MD, PhD, Professor
4
Department of Biology, Medical Genetics and Ecology Kursk State Medical University
5
Research Institute for Genetic and Molecular Epidemiology. Kursk State Medical University
6
3, Karl Marx Street, 305041 Kursk, Russian Federation
7
E-mail: polonikov@rambler.ru
8
Telephone/Fax: +7(4712) 58-81-47
9
Mobile: +7-960-699-19-92
10
Word count: 1225
11
Glutathione is a tripeptide consisting of cysteine, glycine, and glutamate, the most abundant
12
antioxidant preventing oxidative damage of cells from reactive oxygen species (ROS) [1]. Maintenance
13
of highest (millimolar) concentrations of reduced glutathione (GSH) in most cell types highlights its
14
vital and multifunctional roles in the control of various biological processes such as detoxification of
15
foreign and endogenous compounds, protein folding, regeneration of vitamins C and E, antiviral action,
16
mitochondrial function, regulation of cellular proliferation, apoptosis and immune response [1,2].
17
Considering higher rates of serious illness and death from novel coronavirus SARS-CoV-2 infection
18
(COVID-19) among older people and those with comorbidity leading to severe pressure on health
19
services, there is an urgent need to identify effective drugs for disease prevention and treatment [3].
20
Despite a number of publications reporting beneficial effects of glutathione on human health including
21
antiviral defense, the key role of this powerful antioxidant in human physiology and pathology and also
22
a wide spectrum its clinical application remain underestimated.
23
Literature data analysis
24
In order to obtain scientific information regarding a possible link between glutathione deficiency
25
and viral infections, including novel coronavirus SARS-CoV-2 infection, its risk factors, mechanisms
26
and clinical manifestations, a literature search was performed across Pubmed and Google Scholar
27
publications (on April 15, 2020). Over a hundred original articles and reviews have been found and
28
analyzed. As expected, numerous studies reported that endogenous glutathione deficiency attributed to
29
its decreased biosynthesis and/or increased depletion, represents a significant contributor to the
30
pathogenesis of a wide range of human disorders through the mechanisms involving oxidative stress and
31
inflammation. Figure summarizes the most illustrative evidences from biomedical literature indicating
32
that glutathione deficiency is the most likely explanation for epidemiological findings on COVID-19
33
infection regarding the groups at higher risk for severe illness and death, and the restoration of this
34
deficiency can ameliorate clinical manifestations and prognosis significantly in such patients, as it has been
35
clearly demonstrated in other acute respiratory viral infections and pulmonary diseases. In particular, strong
36
evidence from human and animal studies points out the levels of endogenous glutathione are progressively
37
declined with aging making the cells in elderly more susceptible to oxidative damage caused by different
38
environmental factors including viral infections than in the young. The primary deficiency in endogenous
39
glutathione, found in many chronic diseases such as type 2 diabetes, obesity, cancer, cardiovascular,
40
respiratory and liver diseases, may shift per se redox homeostasis in COVID-19 patients towards
41
oxidative stress, thereby exacerbating inflammation in the lung and airways that may lead to acute
42
respiratory distress syndrome (ARDS), multiorgan failure and death. Numerious studies demonstrated
43
that the levels of reduced glutathione in males are lower than in females. This may be a reason why males
44
are more susceptible to oxidative stress and have often poor outcomes from COVID-19 infection than
45
females. Cigarette smoke is known deplete cellular glutathione pool in the airways, thereby exacerbating
46
oxidative damage and inflammation in the lung, more likely requiring intensive medical interventions.
47
Importantly, glutathione is known to protect host immune cells through its antioxidant mechanism and
48
provide the optimal functioning of cells of the immune system. Notably, there are evidences that glutathione
49
inhibits replication of various viruses at different stages of the viral life cycle, thereby decreasing viral load
50
and probably preventing the massive release of inflammatory cells into the lung (“cytokine storm”).
51
Antiviral efficiency of such treatment has been demonstrated by a study of Flora with co-workers [4]
52
showed that six-month preventive administration of N-acetylcysteine (NAC, precursor of glutathione),
53
significantly reduced the incidence of clinically apparent influenza and influenza-like episodes, especially in
54
elderly high-risk individuals. In addition, pathophysiological conditions such as lung cell injury and
55
inflammation found in patients with severe ARDS represents the targets for effective treatment by NAC
56
(Figure).
57
Own observations of COVID-19 cases
58
Our research team from Kursk State Medical University is involved in the project on genetics of
59
redox homeostasis in type 2 diabetes mellitus (T2D) since December, 2016 [5].In April 2020, four
60
patients from the control group, examined in February 2020, contacted with persons with COVID-19
61
confirmed diagnosis (3 patients were quarantined at home and 1 patient was hospitalized in Kursk
62
infectious hospital).Blood samples have been collected from the patients and used to measure total
63
plasma ROS and GSH levels immediately after blood sampling).All four cases were females, non-
64
smokers, without chronic diseases and with confirmed positive PCR-test for COVID-19.Description of
65
the cases is presented below.
66
1.-Patient-M.-(age-34), BMI-23.8 kg/m2. Symptoms (fever-38°C, mild myalgia) appeared on the
67
8th-day after contact with a COVID-19 positive patient and disappeared on the 6th-day of disease
68
without treatment. GSH-0.712 μmol/L, ROS-2.075 μmol/L, ROS/GSH-ratio-2.9.
69
2.-Patient P.-(age-47), BMI 21.0-kg/m2. Symptoms (fever-37.3°C, mild fatigue) appeared on the
70
10th-day after contact with a COVID-19 positive patient and disappeared on the 4th-day of disease
71
without treatment. GSH-0.933 μmol/L, ROS-1.143 μmol/L, ROS/GSH-ratio-1.2.
72
3.-Patient C.-(age-44), BMI 22.5-kg/m2, family history (FH) for diabetes. First symptoms such as
73
fever 37.7°C and air hunger appeared on the 4th-day after contact with a COVID-19 positive patient.
74
Daily fever between 37.1 and 38.5°C, dry cough, hoarseness, significant myalgia and fatigue are
75
persisting to date for 13-days. GSH-0.079- (!)-μmol/L, ROS-2.73-μmol/L, ROS/GSH ratio-34.6-(!).
76
4.-Patient-R.-(age 56), BMI-33.0-kg/m2, PH for diabetes. Symptoms (fever 39°C, severe dry
77
cough, dyspnea, significant fatigue and tachycardia) appeared on the 7th-day after contact with a
78
COVID-19 positive patient, and she was hospitalized with characteristic radiological signs of COVID-
79
19 pneumonia. Clinical symptoms are persisting to date for 11 days. GSH-0.531-μmol/L, ROS-3.677-
80
(!) μmol/L, ROS/GSH-ratio-6.9-(!).
81
Conclusions
82
Based on the literature findings and own observations, a conclusion can be drawn that glutathione
83
deficiency is the most plausible explanation of why people with established risk factors have severe
84
clinical manifestations of COVID-19 infection and increased risk of death. Glutathione deficiency
85
appears to be a common disorder attributed to both environmental and genetic factors including those
86
determining an individual susceptibility to chronic diseases and possibly related with changes in age-
87
and sex-dependent gene expression. Apparently, glutathione deficiency formation takes a long time and
88
occurs predominantly in a winter-spring season associated with an insufficient consumption of fresh
89
vegetables and fruits, natural sources of glutathione [6]. In this regard, a decreased consumption of fresh
90
vegetables and fruits may explain established racial difference in the rate of severe manifestations and
91
death from COVID-19 infection with lower rate among Japanese and Koreans consuming a lot of plant
92
foods and higher rate among African Americans having a limited access to such healthy foods.
93
The antiviral effect of glutathione is clearly non-specific, since GSH is known to inhibit replication of
94
various types of viruses, and therefore there is reason to believe that glutathione is also active against the
95
novel coronavirus infection. Our observations demonstrate that patients with moderate-to-severe COVID-
96
19-infection have lower levels of glutathione, higher ROS levels, and greater ROS/GSH ratio than
97
patients with a mild illness suggesting that coronavirus SARS-CoV-2 cannot actively replicate at higher
98
levels of cellular glutathione, and a lower viral load is manifested by milder clinical symptoms. This
99
makes glutathione a promising drug for etiological treatment of various viral infections. Therefore, oral
100
administration of N-acetylcysteine as a preventive measure against viral infections [6], as well as
101
intravenous injection of NAC or reduced glutathione (GSH is highly bioavailable) in patients with
102
serious illness may be effective options against novel coronavirus SARS-CoV-2 infection. However,
103
clinical trials are needed to objectively assess an efficacy of N-acetylcysteine and reduced glutathione
104
for both the treatment and prevention of this novel viral infection.
105
Conflict of interests: not declared
106
107
References
108
109
1. Forman HJ, Zhang H, Rinna A. Glutathione: overview of its protective roles, measurement, and
110
biosynthesis. Mol Aspects Med. 2009;30(1-2):1-12.
111
2. Pizzorno J. Glutathione! Integr Med (Encinitas). 2014;13(1):8-12.
112
3. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for
113
Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020. doi:10.1001/jama.2020.6019.
114
4. De Flora S, Grassi C, Carati L. Attenuation of influenza-like symptomatology and improvement
115
of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J. 1997;10(7):1535-
116
41.
117
5. Azarova I, Bushueva O, Konoplya A, Polonikov A. Glutathione S-transferase genes and the risk
118
of type 2 diabetes mellitus: Role of sexual dimorphism, gene-gene and gene-smoking interactions in
119
disease susceptibility. J Diabetes. 2018;10(5):398-407.
120
6. Minich DM, Brown BI. A Review of Dietary (Phyto)Nutrients for Glutathione Support.
121
Nutrients. 2019;11(9):E2073.
122
123
124
125
126
127
128
129
130