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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
infection.
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,
e-mail: m.rayman@surrey.ac.uk).
References
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:
10.1093/ajcn/nqaa177.
3. Labunskyy VM, Hateld DL, Gladyshev VN. Selenoproteins:
molecular pathways and physiological roles. Physiol Rev
2014;94(3):739–77.
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
2013;32(5):837–42.
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.
doi: https://doi.org/10.1093/ajcn/nqaa178.
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