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Letters to the Editor
Reply to LA Seale et al.
Dear Editor:
We were very pleased that our nding of an association between
coronavirus disease 2019 (COVID-19) outcome in China and
selenium status (1) was endorsed by Seale and colleagues, based on
their understanding of the likely mechanism by which severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) interacts with the
selenoprotein, cytosolic glutathione peroxidase (GPX1) (2).
GPX1 is low in the hierarchy of selenoprotein expression, hence,
it is among the rst selenoproteins to be depleted in selenium
deciency (3). However, not only does selenium deciency reduce
the activity of GPX1 but it also signicantly compromises the
FIGURE 1 Selenium intake in different countries. The gure is based on data published since 2000, apart from the intake for Venezuela, which is pre-2000
but is included as the value is notably high. Where countries had >1 result, the highest values (dark grey) and the lowest values (pale grey) are shown. Where
there was only 1 result or a median value, it is shown in medium grey. Dietary-intake data are recognized to be of variable quality and accuracy. Adapted from
reference 10, with permission.
activity or concentration of other selenoproteins, including GPX4,
thioredoxin reductase 1–3, and SELENOS, which have antioxidant
or anti-inammatory roles that are important in combatting viral
infection (4). Infection with respiratory viruses, such as SARS-CoV-
2, induces the production of reactive oxygen species and disturbs
the host’s redox balance, triggering pronounced inammation and
subsequent tissue damage (5). Moreover, excessive oxidative stress,
in the absence of adequate GPX1, causes mutation of the viral
genome, leading to the emergence of more virulent strains (6).
A variety of selenoproteins, in addition to GPX1, can counteract
oxidative stress and inammation, as provoked by SARS-CoV-2 (4).
The relative importance of GPX1 in the context of COVID-
19 warrants further consideration. Platelet GPX1 activity, a more
sensitive marker of selenium status than plasma GPX, was measured
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2Letters to the Editor
in a cohort of 119 healthy UK volunteers with a baseline selenium
intake of 55 μg/d (7). GPX1 activity did not change signicantly
on supplementation of the volunteers with 50, 100, or 200 μg
selenium/d, as selenium-yeast, over a period of 10 wk (P=0.16),
implying that an intake of 55 μg/d is sufcient to optimize GPX1
activity (7). We previously reported that the city of Enshi in
Hubei province, with an intake of 550 μg/d, had a cure rate that
was signicantly higher than that of other Hubei cities (1). This
implies the possible existence of a selenium-based mechanism
or mechanisms for overcoming SARS-CoV-2 infection that are
not solely based on optimization of selenoproteins and that may
require a higher selenium intake, at least during the course of the
On a separate issue, echoing our ndings for China (1),
Seale and colleagues also commented on the substantial regional
differences observed in the severity of patient outcomes and case-
fatality rates elsewhere (2). This being the case, they suggest
“probing for selenium concentrations among both symptomatic and
asymptomatic SARS-CoV-2–infected individuals.” However, there
is a problem in measuring selenium status by the usual methods of
serum or plasma selenium in individuals who are already infected,
as serum/plasma selenium concentration will fall as a result of
the systemic inammatory response (8). Erythrocyte selenium is
not affected by inammation and can be determined to give a
reliable measure of selenium status (8). Alternatively, selenium
can be measured in toenail clippings or hair, which will also not
be affected by the inammatory response, at least in the short
term (9).
Despite the difculties in the measurement of selenium status in
infected individuals, it is possible to get some idea of their likely
selenium status by their habitual location, as exposure to selenium
from the diet is quite variable across the world (10). China exhibits
the largest regional difference between maximum and minimum
intake in any country; it may have been that fact that enabled us
to see a signicant difference between Chinese cities with respect
to selenium status and cure rate (1). Of course, it is important
to bear in mind that dietary-intake data are only estimations and
are recognized to be of variable quality and accuracy and also
that selenium supplementation is common, especially in the West
(Figure 1).
Given those caveats, we are in agreement with Seale and
colleagues in hoping that the link between selenoproteins, selenium
species, and SARS-CoV-2 may be able to provide novel insights
into mechanisms that will help us reduce the risk of infection
and mortality from SARS-CoV-2 and other coronaviruses that
may threaten us in the future. If appropriate, the efcacy of
selenium species, which might include ebselen, should be explored
in randomized controlled trials.
JZ and EWT are joint rst authors.
The authors reported no funding associated with this article. The authors
report no conicts of interests.
Jinsong Zhang
Ethan Will Taylor
Kate Bennett
Ramy Saad
Margaret P Rayman
From the State Key Laboratory of Tea Plant Biology and
Utilization, School of Tea and Food Science, Anhui Agricultural
University, Hefei, Anhui, China (JZ); the Department of
Chemistry and Biochemistry, University of North Carolina
Greensboro, Greensboro, NC, USA (EWT); the Surrey Clinical
Trials Unit and Clinical Research Facility, Department of
Clinical and Experimental Medicine, University of Surrey,
Guildford, United Kingdom (KB); Royal Sussex County
Hospital, Brighton, Department of Nutritional Sciences, Faculty
of Health and Medical Sciences, University of Surrey,
Guildford, United Kingdom (RS); and the Department of
Nutritional Sciences, Faculty of Health and Medical Sciences,
University of Surrey, Guildford, United Kingdom (MPR,
1. Zhang J, Taylor EW, Bennett K, Saad R, Rayman MP. Association
between regional selenium status and reported outcome of COVID-19
cases in China. Am J Clin Nutr 2020;111(6):1297–9.
2. Seale LA TD, Berry MJ, Pitts MW. A role for selenium-dependent
GPX1 in SARS-CoV-2 virulence. Am J Clin Nutr 2020, doi:
3. Labunskyy VM, Hateld DL, Gladyshev VN. Selenoproteins:
molecular pathways and physiological roles. Physiol Rev
4. Guillin OM, Vindry C, Ohlmann T, Chavatte L. Selenium,
selenoproteins and viral infection. Nutrients 2019;11(9):2101.
5. Khomich OA, Kochetkov SN, Bartosch B, Ivanov AV. Redox biology
of respiratory viral infections. Viruses 2018;10(8):392.
6. Beck MA, Handy J, Levander OA. Host nutritional status: the neglected
virulence factor. Trends Microbiol 2004;12(9):417–23.
7. Hurst R, Armah CN, Dainty JR, Hart DJ, Teucher B, Goldson AJ,
Broadley MR, Motley AK, Fairweather-Tait SJ. Establishing optimal
selenium status: results of a randomized, double-blind, placebo-
controlled trial. Am J Clin Nutr 2010;91(4):923–31.
8. Stefanowicz FA, Talwar D, O’Reilly DS, Dickinson N, Atkinson
J, Hursthouse AS, Rankin J, Duncan A. Erythrocyte selenium
concentration as a marker of selenium status. Clin Nutr
9. Behne D, Alber D, Kyriakopoulos A. Long-term selenium
supplementation of humans: selenium status and relationships
between selenium concentrations in skeletal muscle and indicator
materials. J Trace Elem Med Biol 2010;24(2):99–105.
10. Winther KH, Rayman MP, Bonnema SJ, Hegedus L. Selenium
in thyroid disorders—essential knowledge for clinicians. Nat Rev
Endocrinol 2020;16(3):165–76.
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Selenium status is an established factor in the incidence, outcome or virulence of various RNA viral infections. Because China has geographic regions that range from extremely high to extremely low selenium intakes, we hypothesized that selenium status might influence the outcome of COVID-19 in these areas. For our analysis, we used reported cumulative case and outcome data for a snapshot of the COVID-19 outbreak, as of 2-18-2020. We found that in the city of Enshi, which is renown for having the highest selenium intakes in China, the cure rate was 3 times as high as that for all the other cities in Hubei Province, where Wuhan is located (p < 0.0001). In contrast, in Heilongjiang Province, where Keshan is located and extreme selenium deficiency is endemic, the death rate was almost 5 times as high as that for all the other Provinces and Municipalities outside of Hubei (p < 0.0001). Finally, for a set of 17 cities outside of Hubei, using published city data on average levels of selenium in human hair (a reliable measure of dietary intake), a significant linear correlation with the cure rate for COVID-19 was observed (R squared = 0.72, P < 0.0001).
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Reactive oxygen species (ROS) are frequently produced during viral infections. Generation of these ROS can be both beneficial and detrimental for many cellular functions. When overwhelming the antioxidant defense system, the excess of ROS induces oxidative stress. Viral infections lead to diseases characterized by a broad spectrum of clinical symptoms, with oxidative stress being one of their hallmarks. In many cases, ROS can, in turn, enhance viral replication leading to an amplification loop. Another important parameter for viral replication and pathogenicity is the nutritional status of the host. Viral infection simultaneously increases the demand for micronutrients and causes their loss, which leads to a deficiency that can be compensated by micronutrient supplementation. Among the nutrients implicated in viral infection, selenium (Se) has an important role in antioxidant defense, redox signaling and redox homeostasis. Most of biological activities of selenium is performed through its incorporation as a rare amino acid selenocysteine in the essential family of selenoproteins. Selenium deficiency, which is the main regulator of selenoprotein expression, has been associated with the pathogenicity of several viruses. In addition, several selenoprotein members, including glutathione peroxidases (GPX), thioredoxin reductases (TXNRD) seemed important in different models of viral replication. Finally, the formal identification of viral selenoproteins in the genome of molluscum contagiosum and fowlpox viruses demonstrated the importance of selenoproteins in viral cycle.
Full-text available
Respiratory viruses cause infections of the upper or lower respiratory tract and they are responsible for the common cold—the most prevalent disease in the world. In many cases the common cold results in severe illness due to complications, such as fever or pneumonia. Children, old people, and immunosuppressed patients are at the highest risk and require fast diagnosis and therapeutic intervention. However, the availability and efficiencies of existing therapeutic approaches vary depending on the virus. Investigation of the pathologies that are associated with infection by respiratory viruses will be paramount for diagnosis, treatment modalities, and the development of new therapies. Changes in redox homeostasis in infected cells are one of the key events that is linked to infection with respiratory viruses and linked to inflammation and subsequent tissue damage. Our review summarizes current knowledge on changes to redox homeostasis, as induced by the different respiratory viruses.
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Dietary recommendations for selenium differ between countries, mainly because of uncertainties over the definition of optimal selenium status. The objective was to examine the dose-response relations for different forms of selenium. A randomized, double-blind, placebo-controlled dietary intervention was carried out in 119 healthy men and women aged 50-64 y living in the United Kingdom. Daily placebo or selenium-enriched yeast tablets containing 50, 100, or 200 microg Se ( approximately 60% selenomethionine), selenium-enriched onion meals ( approximately 66% gamma-glutamyl-methylselenocysteine, providing the equivalent of 50 microg Se/d), or unenriched onion meals were consumed for 12 wk. Changes in platelet glutathione peroxidase activity and in plasma selenium and selenoprotein P concentrations were measured. The mean baseline plasma selenium concentration for all subjects was 95.7 +/- 11.5 ng/mL, which increased significantly by 10 wk to steady state concentrations of 118.3 +/- 13.1, 152.0 +/- 24.3, and 177.4 +/- 26.3 ng/mL in those who consumed 50, 100, or 200 microg Se-yeast/d, respectively. Platelet glutathione peroxidase activity did not change significantly in response to either dose or form of selenium. Selenoprotein P increased significantly in all selenium intervention groups from an overall baseline mean of 4.99 +/- 0.80 microg/mL to 6.17 +/- 0.85, 6.73 +/- 1.01, 6.59 +/- 0.64, and 5.72 +/- 0.75 microg/mL in those who consumed 50, 100, or 200 microg Se-yeast/d and 50 microg Se-enriched onions/d, respectively. Plasma selenoprotein P is a useful biomarker of status in populations with relatively low selenium intakes because it responds to different dietary forms of selenium. To optimize the plasma selenoprotein P concentration in this study, 50 microg Se/d was required in addition to the habitual intake of approximately 55 microg/d. In the context of established relations between plasma selenium and risk of cancer and mortality, and recognizing the important functions of selenoprotein P, these results provide important evidence for deriving estimated average requirements for selenium in adults. This trial was registered at as NCT00279812.
In the 1990s, selenium was identified as a component of an enzyme that activates thyroid hormone; since this discovery, the relevance of selenium to thyroid health has been widely studied. Selenium, known primarily for the antioxidant properties of selenoenzymes, is obtained mainly from meat, seafood and grains. Intake levels vary across the world owing largely to differences in soil content and factors affecting its bioavailability to plants. Adverse health effects have been observed at both extremes of intake, with a narrow optimum range. Epidemiological studies have linked an increased risk of autoimmune thyroiditis, Graves disease and goitre to low selenium status. Trials of selenium supplementation in patients with chronic autoimmune thyroiditis have generally resulted in reduced thyroid autoantibody titre without apparent improvements in the clinical course of the disease. In Graves disease, selenium supplementation might lead to faster remission of hyperthyroidism and improved quality of life and eye involvement in patients with mild thyroid eye disease. Despite recommendations only extending to patients with Graves ophthalmopathy, selenium supplementation is widely used by clinicians for other thyroid phenotypes. Ongoing and future trials might help identify individuals who can benefit from selenium supplementation, based, for instance, on individual selenium status or genetic profile.
Selenium is an essential micronutrient with important functions in human health and relevance to several pathophysiological conditions. The biological effects of selenium are largely mediated by selenium-containing proteins (selenoproteins) that are present in all three domains of life. Although selenoproteins represent diverse molecular pathways and biological functions, all these proteins contain at least one selenocysteine (Sec), a selenium-containing amino acid, and most serve oxidoreductase functions. Sec is cotranslationally inserted into nascent polypeptide chains in response to the UGA codon, whose normal function is to terminate translation. To decode UGA as Sec, organisms evolved the Sec insertion machinery that allows incorporation of this amino acid at specific UGA codons in a process requiring a cis-acting Sec insertion sequence (SECIS) element. Although the basic mechanisms of Sec synthesis and insertion into proteins in both prokaryotes and eukaryotes have been studied in great detail, the identity and functions of many selenoproteins remain largely unknown. In the last decade, there has been significant progress in characterizing selenoproteins and selenoproteomes and understanding their physiological functions. We discuss current knowledge about how these unique proteins perform their functions at the molecular level and highlight new insights into the roles that selenoproteins play in human health.
Background & aims: Plasma selenium concentration and glutathione peroxidase (GPx) activity are commonly used as markers of selenium nutritional status. However, plasma selenium concentrations fall independently of selenium status during the acute phase response and GPx is analytically problematic. The assay for erythrocyte selenium is robust and concentrations are unaffected by the systemic inflammatory response. This study was performed to investigate the validity of erythrocyte selenium measurement in assessing selenium status. Methods: C-reactive protein (CRP), plasma and erythrocyte selenium concentrations and GPx activity were measured in 96 women from two regions of Malawi with low and high selenium dietary intakes. CRP and plasma and erythrocyte selenium was measured in 91 critically ill patients with a systemic inflammatory response. Results & conclusions: The median CRP value of all subjects from Malawi was 4.2 mg/L indicating no inflammation. The median CRP value for the critically ill patients was 126 mg/L indicating this group was inflamed. In the non-inflamed population there was a strong positive correlation (r = 0.95) between erythrocyte and plasma selenium and a strong positive correlation (r = 0.77) between erythrocyte selenium and erythrocyte GPx up to 6.10 nmol/g Hb after which maximal activity was reached. In the inflamed population, plasma selenium was low, erythrocyte selenium was normal and there was a weak correlation (r = 0.30) between selenium concentrations in plasma and erythrocytes. This demonstrates that plasma selenium is affected by the inflammatory response while erythrocyte selenium concentration is unaffected and can be used to reliably assess selenium status across a wide range of selenium intakes.
Supplementation with elevated doses of l-selenomethionine (SeM) or selenium-enriched yeast that contains SeM as the main selenium species is frequently used as a protective or therapeutic measure. Information on the effects of long-term selenium supplementation on the body selenium status is, however, rather scarce. We therefore investigated fifteen male test persons who had taken selenium yeast and/or SeM supplements in medium doses of 62.5-125 microg Se/day or high doses of 200-262.5 microg Se/day for periods ranging from 1 year to 24 years. Seven non-supplemented men served as controls. As skeletal muscle is the main selenium pool, thigh muscle biopsy samples were taken. The selenium concentrations in these biopsies and in samples of the indicator materials blood, blood plasma, blood cells, head hair and toenails were determined by neutron activation analysis. Compared with the controls, the muscle selenium level was raised with additional selenium supplementation, but the relative increase in the mean muscle selenium concentration (by factors of about 1.6 and 2 for the medium and high doses, respectively) was lower than that in the selenium intake. Highly significant correlations found between the selenium concentrations in muscle and whole blood (R=0.90), red blood cells (R=0.91), blood plasma (R=0.87), head hair (R=0.89) and toenails (R=0.85) show that in humans supplemented in this way the selenium status can be assessed in a relatively easy way by analysis of the selenium retention in these indicator materials.
The emergence of new infectious diseases and old diseases with new pathogenic properties is a burgeoning worldwide problem. Severe acute respiratory syndrome (SARS) and acquired immune deficiency syndrome (AIDS) are just two of the most widely reported recent emerging infectious diseases. What are the factors that contribute to the rapid evolution of viral species? Various hypotheses have been proposed, all involving opportunities for virus spread (for example, agricultural practices, climate changes, rainforest clearing or air travel). However, the nutritional status of the host, until recently, has not been considered a contributing factor to the emergence of infectious disease. In this review, we show that host nutritional status can influence not only the host response to the pathogen, but can also influence the genetic make-up of the viral genome. This latter finding markedly changes our concept of host-pathogen interactions and creates a new paradigm for the study of such phenomena.