Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients
Alexey Polonikov*
Cite this: ACS Infect. Dis. 2020, 6, 7, 1558–1562
Publication Date:May 28, 2020
https://doi.org/10.1021/acsinfecdis.0c00288
Copyright © 2020 American Chemical Society
SUBJECTS: Nutrition,Infectious diseases,Organic compounds,Antioxidants,Oxidative stress
| Abstract 요약 고령자와 기저 질환이 있는 사람들 사이에서 코로나 바이러스 SARS-CoV-2 (COVID-19) 감염으로 인한 심각한 질병 및 사망률이 높다는 것은, 나이와 질병 관련 생물적 과정이 코로나 바이러스 SARS-CoV-2 같은 감염원 등 환경 스트레스 요인에 더 민감하게 됨을 시사합니다. 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. 특히, 손상된 산화환원 항상성과 관련된 산화스트레스는 다양한 환경적 모욕에 대한 개인 감수성을 증가시키는 중요한 생물적 과정으로 보입니다. 이 관점의 목적은 (1) COVID-19 감염 및 질병 발병에 대한 개인 반응을 결정하는 데 글루타티온의 중요한 역할과 (2) COVID-19 질병의 치료 및 예방 수단으로 글루타티온을 사용하는 타당성을 정당화하는 것입니다. 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. 글루타티온 결핍이 COVID-19 환자의 심각한 증상과 사망에 대한 가장 그럴듯한 설명이라는 가설은 철저한 문헌 분석과 관찰을 기반으로 제안되었습니다. 이 가설은 COVID-19 감염의 심각한 징후와 높은 사망 위험을 결정하는 위험 요인에 대한 역학 데이터의 수수께끼를 풀고 질병의 효과적 치료 및 예방을 위한 실질적 기회를 열어줍니다. 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. |
NOTE
이 기사는 ACS COVID-19 하위 집합을 통해 제한되지 않은 RESEARCH 재사용 및 분석을 위해 원본 출처를 인정하는 모든 형태 또는 수단으로 제공됩니다.
이러한 허가는 세계보건기구 (WHO)가 전 세계적으로 유행하는 COVID-19 선언 기간 동안 부여됩니다.
This article is made available via the ACS COVID-19 subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
글루타티온 전문
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신종 코로나 바이러스 SARS-CoV-2 (COVID-19)는 전세계에 계속 퍼져 점점 더 많은 사람들에게 영향을 주고 있습니다;
따라서 질병 예방 및 치료를 위한 효과적 약물 식별이 필요합니다.
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.
SARS-CoV-2에 감염된 대다수 사람들은 무증상, 경증, 중등도 질환을 앓고 있으며, 환자의 14%는 중증 그리고 5%는 위험 상태입니다.
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)
노인과 기저 질환이 있는 사람들의 COVID-19 중증 질환 및 사망률이 높다는 것은, 연령 및 질병 관련 생물적 과정이 그러한 개인이 코로나 바이러스 SARS-CoV-2와 같은 감염원 등 환경 스트레스 요인에 더 민감하게 만든다는 것을 시사합니다.
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.
특히, 손상된 산화환원 항상성과 관련된 산화스트레스는 다양한 환경적 공격에 대한 개인 감수성을 증가시키는 중요한 생물학적 과정으로 보입니다.
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)
산화스트레스는 활성 산소 종 (ROS)의 증가된 생산과 생물학적 시스템이 반응성 중간체를 해독하거나 그로 인한 손상을 복구할 수 없는 불균형을 반영하는 비특이적 병리적 상태입니다.
특히 ROS는 노화와 밀접한 관련이 있는데, 노화에 따른 손상에 대한 스트레스 반응을 매개하기 때문입니다.
Notably, ROS are closely related with aging because they mediate a stress response to age-dependent damage.(3)
ROS 생성 증가 및/또는 항산화 방어 감소로 인한 산화스트레스 및 관련 염증이 다양한 만성질환 발병에 기여한다는 개념을 뒷받침하는 증거가 늘어나고 있는데, COVID-19 환자의 심각한 질병 및 사망 위험을 증가시키는 것으로 알려진 당뇨병 및 심혈관 및 호흡기 질환을 포함합니다.
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)
숙주 항산화 반응의 바이러스에 의한 조절이 질병 진행을 결정하는 중요한 결정인자로 알려져 있습니다.
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)
이와 관련하여, 산화스트레스로부터 보호하는 항산화 방어 시스템이 감염원에 대한 비특이적 민감성 또는 내성의 기전을 이해하는 맥락에서 큰 관심을 보입니다.
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.
글루타티온 (시스테인, 글리신, 글루타메이트로 구성된 트리펩타이드)은 ROS로 인한 세포의 산화적 손상에 대한 항산화 방어에 중요한 역할을 하는 가장 풍부한 분자량 항산화제이며, 전신에 필수적인 다양한 대사경로 조절에도 관여합니다.
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)
대부분의 세포 유형에서 감소된 글루타티온 (GSH)의 최고 (밀리몰) 농도를 유지하는 것은, 외래 및 체내 화합물의 해독, 단백질 접힘, 비타민 C와 E 재생, 등미토콘드리아 기능 유지, 항 바이러스 방어, 세포증식 조절, 세포사멸 및 면역반응 조절 등 다양한 생물적 과정을 제어하는 데 있어 중요하고 다기능적 역할을 강조합니다.
인간의 건강에 대한 글루타티온의 유익한 효과를 보고하는 많은 출판물에도 불구하고, 인간 생리학 및 병리학 및 임상 적용에서 이 강력한 항산화제의 핵심 역할은 여전히 과소 평가되고 있습니다.
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.
이 관점의 목적은
(1) COVID-19 감염 및 질병 발병에 대한 개인의 반응을 결정하는 데 글루타티온의 중요한 역할과
(2) COVID-19 질병의 치료 및 예방을 위한 수단으로 글루타티온을 사용하는 타당성을 정당화하는 것입니다.
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.
Does Glutathione Deficiency Worsen COVID-19 Prognosis through the Risk Factors?
글루타티온 결핍은 위험요소를 통해 COVID-19 예후를 악화시킵니까?
많은 연구에 따르면 생합성 감소 및/또는 GSH 고갈 증가로 인한 내인성 글루타티온 결핍은 산화스트레스 및 염증과 관련된 메커니즘을 통해 다양한 질병의 발병에 중요한 기여합니다.
그림1은 체내 글루타티온 결핍을 일으키는 가장 일반적 원인과이 결핍이 심각한 COVID-19 질병의 발병에 기여할 수있는 메커니즘을 요약합니다.
Numerous studies report that endogenous glutathione deficiency attributed to decreased biosynthesis and/or increased depletion of GSH represents a significant contributor to the pathogenesis of various diseases through mechanisms involving oxidative stress and inflammation. Figure 1 summarizes the most common causes responsible for endogenous glutathione deficiency and also the mechanisms through which this deficiency may contribute to the pathogenesis of severe COVID-19 disease.
Figure 1
Figure 1. Factors responsible for endogenous glutathione deficiency and the mechanisms through which this deficiency may contribute to COVID-19 pathogenesis and outcomes. The bottom of the figure shows that the risk factors for severe COVID-19 infection are associated with decrease/depletion of intracellular glutathione. The top of the figure shows the potential mechanisms through which glutathione deficiency could influence clinical manifestations and outcomes in COVID-10 disease. The numbers in brackets indicate PubMed references (PMID).
Age is a well-recognized risk factor for severe illness, complications, and death from COVID-19 infection.(8) Interestingly, animal and human studies indicate that the levels of endogenous glutathione progressively decline with aging, thereby making cells in the elderly more susceptible to oxidative damage caused by different environmental factors compared to younger individuals.
Comorbidity is considered one of the major risk factors responsible for poor prognosis in COVID-19 patients.(5) Interestingly, the deficiency in endogenous glutathione is common in individuals with chronic diseases as well as in individuals with a worsening prognosis of COVID-19. This means that decreased levels of glutathione occurring in COVID-19 patients with chronic diseases could be a triggering factor that shifts redox homeostasis toward oxidative stress, thereby exacerbating lung inflammation and leading to acute respiratory distress syndrome (ARDS), multiorgan failure, and death.
Sex-related COVID-19 mortality is one of the common epidemiologic findings around the globe,(9) suggesting sexual dimorphism in susceptibility to severe illness. It has been observed that men are significantly more likely to suffer severe effects of COVID-19 infection and experience a higher mortality rate that women.(9) In addition, men have lower plasma levels of reduced glutathione (GSH) than women, making men more susceptible to oxidative stress and inflammation.
Smoking is also considered a risk factor for severe complications and death from COVID-19.(10) Cigarette smoke is known to deplete the cellular glutathione pool in the airways, exacerbating oxidative damage and inflammation in the lung, which is likely the reason why smokers with COVID-19 more likely require intensive medical interventions.
Dietary factors may also contribute to endogenous glutathione deficiency in patients with severe COVID-19 illness. In particular, an insufficient consumption of fresh vegetables and fruits, natural sources of glutathione, seems to be an important but not yet established risk factor responsible for glutathione deficiency in patients with severe COVID-19 illness.
Thus, the relationship between risk factors and serious manifestations and death in COVID-19 patients could be attributable to a common cause, glutathione deficiency.
나이는 COVID-19 감염으로 인한 심각한 질병, 합병증 및 사망에 대한 잘 알려진 위험 요소입니다. (8)
흥미롭게도 동물 및 인간 연구에 따르면 내인성 글루타티온 수치가 노화에 따라 점진적으로 감소하여 노인의 세포를 더 많이 만듭니다.
젊은 사람에 비해 다양한 환경 요인으로 인한 산화 손상에 민감합니다.
동반 질환은 COVID-19 환자의 예후 불량의 원인이되는 주요 위험 요인 중 하나로 간주됩니다. (5)
흥미롭게도 체내 글루타티온 결핍은 만성질환이 있는 개인뿐 아니라 COVID-19의 예후가 악화되는 개인에게 흔합니다.
이는 만성 질환을 앓고있는 COVID-19 환자에서 발생하는 글루타티온 수치 감소가 산화환원 항상성을 산화스트레스로 전환시켜 폐 염증을 악화시키고 급성 호흡곤란 증후군 (ARDS), 다기관 부전 및 사망을 유발하는 요인이 될 수 있음을 의미합니다.
성 관련 COVID-19 사망률은 전 세계적으로 흔히 발견되는 역학적 발견 중 하나이며 (9) 심각한 질병에 대한 감수성에서 성적 이형성을 시사합니다.
남성은 COVID-19 감염의 심각한 영향을 받고 여성보다 사망률이 더 높은 것으로 나타났습니다. (9)
또한 남성은 여성보다 혈장 감소 된 글루타티온 (GSH) 수치가 낮아 남성이됩니다.
산화 스트레스와 염증에 더 취약합니다.
흡연은 또한 COVID-19로 인한 심각한 합병증과 사망의 위험 요소로 간주됩니다. (10)
담배 연기는기도의 세포 글루타티온 풀을 고갈시켜 폐의 산화 손상과 염증을 악화시키는 것으로 알려져 있습니다.
COVID-19로 인해 집중적 인 의료 개입이 필요할 가능성이 높습니다.
식이 요인은 또한 중증 COVID-19 질환 환자의 체내 글루타티온 결핍에 기여할 수 있습니다.
특히, 글루타티온의 천연 공급 원인 신선한 야채와 과일의 부족한 섭취는 중증 COVID-19 질환 환자의 글루타티온 결핍을 일으키는 중요하지만 아직 확립되지 않은 위험 요소 인 것으로 보입니다.
따라서 COVID-19 환자의 위험 요인과 심각한 증상 및 사망 사이의 관계는 일반적 원인인 글루타티온 결핍에 기인 할 수 있습니다.
중증 COVID-19 질병의 주요 원인은 무엇입니까: 글루타티온 또는 비타민 D 결핍?
What Is the Primary Cause of Severe COVID-19 Illness: Glutathione or Vitamin D Deficiency?
The novel hypothesis that vitamin D (VD) deficiency is responsible for severe manifestations and death in COVID-19 patients has been proposed(11) and is actively being discussed by the scientific community. Several studies reported that glutathione levels positively correlate with active vitamin D.(12,13) It has also been found that lower levels of l-cysteine (a rate-limiting precursor of GSH) and GSH correlated with lower vitamin D binding protein (VDBP) and VD levels in T2D patients(14) . l-cysteine supplementation is known to improve GSH status through upregulation of expression of VDBP, vitamin D 25-hydroxylase, and vitamin D receptor, thereby increasing vitamin D levels and decreasing inflammatory biomarkers in diabetic rats.(15) Interestingly, a recent experimental study(16) showed that GSH deficiency and the associated increased oxidative stress epigenetically alters vitamin D regulatory genes and, as a result, the suppressed gene expression decreases VD biosynthesis, ultimately leading to a secondary deficiency of vitamin D. It is important to note that the replenishment of GSH by l-cysteine treatment beneficially altered epigenetic enzymes methyltransferases and increased the expression of VD-metabolism genes. This study provides important information that glutathione is essential for the control of endogenous vitamin D biosynthesis and demonstrates potential benefits of GSH treatment in reducing the deficiency of vitamin D. Taken together, these findings suggest that glutathione deficiency rather than vitamin D deficiency is a primary cause underlying biochemical abnormalities, including the decreased biosynthesis of vitamin D, and is responsible for serious manifestations and death in COVID-19 patients.
비타민 D (VD) 결핍이 COVID-19 환자의 심각한 증상과 사망의 원인이라는 새로운 가설이 제안되었으며 (11) 과학계에서 활발히 논의되고 있습니다. 여러 연구에서 글루타티온 수치가 활성 비타민 D와 긍정적 상관관계가 있다고보고했습니다. (12,13)
l- 시스테인 (GSH의 속도 제한 전구체) 및 GSH 수치가 낮은 비타민 D 결합 단백질 (VDBP)과 상관 관계가있는 것으로 밝혀졌습니다. ) 및 T2D 환자의 VD 수준 (14).
l- 시스테인 보충제는 VDBP, 비타민 D 25- 하이드록실라제 및 비타민 D 수용체의 발현을 상향조절하여 GSH 상태를 개선하여 당뇨병 쥐의 비타민 D 수준을 높이고 염증성 바이오 마커를 감소시키는 것으로 알려져 있습니다.(15)
흥미롭게도 최근 실험 연구 (16)은 GSH 결핍과 관련된 산화 스트레스 증가가 비타민 D 조절 유전자를 후 성적으로 변화시키고 결과적으로 억제된 유전자 발현이 VD 생합성을 감소시켜 궁극적으로 비타민 D의 2 차 결핍으로 이어진다는 것을 보여주었습니다.
l- 시스테인 처리에 의한 GSH의 보충은 후성 유전 효소인 메틸 트랜스퍼 라제를 유익하게 변경하고 VD- 대사 유전자의 발현을 증가시켰다.
이 연구는 글루타티온이 내인성 비타민 D 생합성 조절에 필수적이라는 중요한 정보를 제공하고 비타민 D 결핍을 줄이는 데있어 GSH 치료의 잠재적 이점을 보여줍니다.
이러한 결과를 종합하면 비타민 D 결핍보다는 글루타티온 결핍이 주요 원인임을 시사합니다.
비타민 D의 생합성 감소 등 근본적 생화학적 이상이며 COVID-19 환자의 심각한 증상과 사망을 초래합니다.
글루타티온의 항바이러스, 항 염증 및 항 응고 특성
Antiviral, Anti-Inflammatory, and Anticoagulant Properties of Glutathione
Several studies indicate that higher levels of glutathione may improve an individual’s responsiveness to viral infections. In particular, glutathione is known to protect host immune cells through its antioxidant mechanism and is also responsible for optimal functioning of a variety of cells that are part of the immune system. It is important to note that there is evidence that glutathione inhibits replication of various viruses at different stages of the viral life cycle (Figure 1), and this antiviral property of GSH seems to prevent increased viral loads and the subsequent massive release of inflammatory cells into the lung (“cytokine storm”).
The antiviral activity of glutathione was demonstrated in a study of De Flora et al.(17) who showed that a 6 month preventive administration of N-acetylcysteine (NAC, glutathione precursor) significantly reduced the incidence of clinically apparent influenza and influenza-like episodes, especially in elderly high-risk individuals. In addition, pathophysiological conditions such as lung cell injury and inflammation in patients with severe ARDS were identified as the targets of NAC treatment. In particular, the deficiency of reduced glutathione in the alveolar fluid in ARDS patients was found to enhance lung cell injury by ROS/oxidative stress and inflammation, and this damage could be effectively prevented and treated by the administration of NAC (Figure 1).Glutathione deficiency could also promote the increased activation of von Willebrand Factor causing coagulopathy in COVID-19 patients.
여러 연구에 따르면 글루타티온 수치가 높으면 바이러스 감염에 대한 개인의 반응성이 향상 될 수 있습니다.
특히, 글루타티온은 항산화 메커니즘을 통해 숙주 면역 세포를 보호하는 것으로 알려져 있으며 면역 체계의 일부인 다양한 세포의 최적 기능을 담당하기도합니다.
글루타티온이 바이러스 수명주기의 여러 단계에서 다양한 바이러스의 복제를 억제한다는 증거가 있으며 (그림 1), GSH의 이러한 항 바이러스 특성은 증가 된 바이러스 부하와 이에 따른 염증 세포의 대량 방출을 방지하는 것으로 보입니다. 폐 ( "사이토 카인 폭풍").
글루타티온의 항바이러스 활성은 N- 아세틸 시스테인 (NAC, 글루타티온 전구체)의 6개월 예방 투여가 임상적으로 명백한 인플루엔자 및 인플루엔자 유사 에피소드의 발생률을 현저히 감소 시켰음을 보여준 De Flora et al. (17)의 연구에서 입증되었습니다.
, 특히 고위험 노인의 경우.
또한 심각한 ARDS 환자의 폐 세포 손상 및 염증과 같은 병태 생리적 상태가 NAC 치료의 표적으로 확인되었습니다.
특히 ARDS 환자의 폐포 액에서 감소된 글루타티온의 결핍은 ROS/산화스트레스 및 염증에 의한 폐 세포 손상을 증가시키는 것으로 밝혀졌으며, 이 손상은 NAC 투여로 효과적으로 예방 및 치료할 수 있습니다 (그림 1).
결핍은 또한 COVID-19 환자에서 응고 병증을 유발하는 폰 빌레 브란트 인자의 활성화 증가를 촉진할 수 있습니다.
글루타티온 결핍은 COVID-19 질병을 악화시킵니다: 내 관찰
Glutathione Deficiency Exacerbates COVID-19 Illness: My Observations
Kursk State Medical University는 2016년 12월부터 2형 당뇨병 (T2D)에서 산화환원 항상성 유전학 프로젝트에 참여했습니다.
2020년 4월, 대조군에서 4 명의 환자가 COVID-19에 걸린 것으로 확인되었습니다.
환자로부터 혈액 샘플을 수집하여 혈액 샘플링 직후 총 혈장 ROS 및 GSH 수준을 측정하는 데 사용되었습니다.
4명의 환자는 모두 여성, 비 흡연자, 만성 질환이 없었습니다.
표 1은 사례에 대한 설명입니다.
중등도 및 중증 COVID-19 질환 환자는 경증 환자보다 혈장에서 글루타티온 수치가 낮고 ROS 및 ROS / GSH 비율이 더 높았으며, 이는 심각한 질병 증상이 있는 환자에서 글루타티온 결핍 및 산화스트레스 징후를 명확하게 나타냅니다.
특히, 중증 질환과 현저한 글루타티온 감소가 있는 환자만이 여전히 심하게 아프고 GSH 수치가 높거나 중간 정도 인 다른 환자는 회복되었습니다.
Kursk State Medical University has been involved in a project on genetics of redox homeostasis in type 2 diabetes (T2D) since December, 2016. In April 2020, four patients from the control group were confirmed to have COVID-19. Blood samples were collected from the patients and used to measure total plasma ROS and GSH levels immediately after blood sampling. All four patients were females, nonsmokers, and without chronic diseases. Table 1 shows a description of the cases. Patients with moderate and severe COVID-19 illness had lower levels of glutathione and higher ROS and ROS/GSH ratio in plasma than patients with mild disease, clearly indicating glutathione deficiency and oxidative stress signs in patients with serious disease manifestations. Notably, only the patient with severe illness and a marked glutathione decrease is still severely sick, whereas the other patients with high/moderate levels of GSH have recovered.
Table 1. Clinical and Laboratory Characteristics of Four COVID-19 Patientsa
표 1. 4 명의 COVID-19 환자의 임상 및 실험실 특성
| cases | disease severity | BMI, kg/m2/family history (FH) | day of clinical onset after contact with infected patient | clinical symptoms | day when symptoms disappeared | parameters of redox status, μmol/Lb |
| 1. female M. (age 34) | mild | 23.8 | 8 | fever 38 °C, mild myalgia | 6 | GSH, 0.712; ROS, 2.075; ROS/GSH ratio, 2.9 |
| 2. female P. (age 47) | mild | 21.0 | 10 | fever 37.3 °C, mild fatigue | 4 | GSH, 0.933; ROS, 1.143; ROS/GSH ratio, 1.2 |
| 3. female C. (age 44) | severe | 22.5, FH for diabetes | 4 | daily fever between 37.1 and 38.5 °C, dry cough, hoarseness, significant myalgia and fatigue (radiographic findings of pneumonia) | still sick, 24th day of illness (03.05.2020) | GSH, 0.079 (!); ROS, 2.73; ROS/GSH ratio, 34.6 (!) |
| 4. female R. (age 56) | moderate-to-severe | 33.0, FH for diabetes | 7 | fever up to 39 °C, a severe dry cough, dyspnea, significant fatigue and tachycardia (radiographic findings of pneumonia) | 16 | GSH, 0.531; ROS, 3.677 (!); ROS/GSH ratio, 6.9 (!) |
aAll four cases were nonsmokers without a history of chronic diseases. COVID-19 infection was confirmed by a PCR test in all cases.
bThe parameters were measured 2 months before the patients became infected with coronavirus SARS-CoV-2.
Hypothesis
Endogenous glutathione deficiency appears to be a crucial factor enhancing SARS-CoV-2-induced oxidative damage of the lung and, as a result, leads to serious manifestations, such as acute respiratory distress syndrome, multiorgan failure, and death in COVID-19 patients. When the antiviral activity of GSH is taken into account, individuals with glutathione deficiency seem to have a higher susceptibility for uncontrolled replication of SARS-CoV-2 virus and thereby suffer from an increasing viral load. The severity of clinical manifestations in COVID-19 patients is apparently determined by the degree of impaired redox homeostasis attributable to the deficiency of reduced glutathione and increased ROS production. This assumption can be supported by our findings. In particular, COVID-19 patients with moderate and severe illness had lower levels of glutathione, higher ROS levels, and greater redox status (ROS/GSH ratio) than COVID-19 patients with a mild illness. Long-term and severe manifestations of COVID-19 infection in one of our patients with marked glutathione deficiency suggest that the degree of glutathione decrease correlates negatively with viral replication rate and that an increasing viral load exacerbates oxidative damage of the lung. This finding suggests that the virus cannot actively replicate at higher levels of cellular glutathione, and therefore, milder clinical symptoms are observed with lower viral loads.
Glutathione deficiency is an acquired condition attributable to decreased biosynthesis and/or increased depletion of the endogenous GSH pool influenced by risk factors such as aging, male sex, comorbidity, and smoking alone or in combinations. Glutathione deficiency in COVID-19 patients with serious illness may also be a result of decreased consumption of fresh vegetables and fruits (especially during winter and spring seasons), which contributes to over 50% of dietary glutathione intake.The hypothesis suggests that SARS-CoV-2 virus poses a danger only for people with endogenous glutathione deficiency, regardless which of the factors aging, chronic disease comorbidity, smoking or some others were responsible for this deficit. The hypothesis provides novel insights into the etiology and mechanisms responsible for serious manifestations of COVID-19 infection and justifies promising opportunities for effective treatment and prevention of the illness through glutathione recovering with N-acetylcysteine and reduced glutathione.
Since the antiviral effect of glutathione is nonspecific, there is reason to believe that glutathione is also active against SARS-CoV-2. Therefore, restoration of glutathione levels in COVID-19 patients would be a promising approach for the management of the novel coronavirus SARS-CoV-2. Notably, long-term oral administration of N-acetylcysteine has already been tested as an effective preventive measure against respiratory viral infections.(1) N-Acetylcysteine is widely available, safe, and cheap and could be used in an “off-label” manner. Moreover, parenteral injection of NAC or reduced glutathione (GSH is more bioavailable than NAC) could be an efficient therapy for COVID-19 patients with serious illness. Horowitz et al.(18) just published a paper confirming this hypothesis: the authors reported the efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia. Nonetheless, the proposed hypothesis has to be confirmed in larger epidemiological and experimental studies, and also, clinical trials are needed to objectively assess the efficacy of N-acetylcysteine and reduced glutathione for the treatment and prevention of COVID-19 infection.
The author declares no competing financial interest.
Author Information
Corresponding Author
Alexey Polonikov - Department of Biology, Medical Genetics and Ecology and Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russian Federation;
http://orcid.org/0000-0001-6280-247X; Email: polonikov@rambler.ru
Notes
The author declares no competing financial interest.
Acknowledgments
I am grateful to my colleague Dr. Iuliia Azarova at Kursk State Medical University for sharing clinical and laboratory data of the patients with me.
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