Selenium and selenoproteins in viral infection with potential relevance to COVID-19

Abstract

Selenium is a trace element essential to human health largely because of its incorporation into selenoproteins that have a wide range of protective functions. Selenium has an ongoing history of reducing the incidence and severity of various viral infections; for example, a German study found selenium status to be significantly higher in serum samples from surviving than non-surviving COVID-19 patients. Furthermore, a significant, positive, linear association was found between the cure rate of Chinese patients with COVID-19 and regional selenium status. Moreover, the cure rate continued to rise beyond the selenium intake required to optimise selenoproteins, suggesting that selenoproteins are probably not the whole story. Nonetheless, the significantly reduced expression of a number of selenoproteins, including those involved in controlling ER stress, along with increased expression of IL-6 in SARS-CoV-2 infected cells in culture suggests a potential link between reduced selenoprotein expression and COVID-19-associated inflammation. In this comprehensive review, we describe the history of selenium in viral infections and then go on to assess the potential benefits of adequate and even supra-nutritional selenium status. We discuss the indispensable function of the selenoproteins in coordinating a successful immune response and follow by reviewing cytokine excess, a key mediator of morbidity and mortality in COVID-19, and its relationship to selenium status. We comment on the fact that the synthetic redox-active selenium compound, ebselen, has been found experimentally to be a strong inhibitor of the main SARS-CoV-2 protease that enables viral maturation within the host. That finding suggests that redox-active selenium species formed at high selenium intake might hypothetically inhibit SARS-CoV-2 proteases. We consider the tactics that SARS-CoV-2 could employ to evade an adequate host response by interfering with the human selenoprotein system. Recognition of the myriad mechanisms by which selenium might potentially benefit COVID-19 patients provides a rationale for randomised, controlled trials of selenium supplementation in SARS-CoV-2 infection.

Keywords: COVID-19; Ebselen; Redox-active selenium species; SARS-CoV-2; Selenium; Selenoproteins.

Fig. 1

Correlation between COVID-19 cure rate in 17 cities outside Hubei on Feb 18, 2020, and city population selenium status (hair selenium concentration) analysed using weighted linear regression. Each data point represents the cure rate, calculated as percentage of patients hospitalized with SARS-CoV-2 deemed to be cured*. The size of the marker is proportional to the number of cases (adapted from Am J Clin Nutr [7] with permission). From the graph of Se intake vs hair Se concentration, Supplemental Figure 1, Se_intake = 232.98 Se_hair – 44.521,allowing the calculation of corresponding values of selenium intake and hair concentration (Supplemental Table 3). Thus value A represents the hair concentration corresponding to an intake of 55 µg/d where platelet GPX1 activity is maximised [58], value B represents the hair concentration corresponding to an intake of 105 µg/d where SELENOP concentration is maximised [58], and value C is the hair selenium concentration (1.0 mg/kg) at the maximum cure rate in the investigated cities which corresponds to an intake of 188 µg/d.*Cured patients are those in whom temperature has returned to normal for more than 3 days, respiratory symptoms are significantly improved, lung imaging shows significant reduction of inflammation, negative nucleic acid test of respiratory pathogen on two consecutive occasions with a sampling interval of at least 1 day.

Fig. 2

Hypothesised interaction of selenium compounds with SARS-CoV-2 consisting of cycling of redox-active selenium compounds in various cells (lower panel) and the presence of volatile redox-active selenium compounds in the lung (upper panel). GS-Se-SG, selenodiglutathione; CH₃SeOH, methylseleninic acid; CH₃SeSeCH₃, dimethyldiselenide; H₂Se, hydrogen selenide; GS-SeH, glutathione selenopersulfide; CH₃SeH, methylselenol; GSH, glutathione; GR, GSH reductase; GRX, glutaredoxin; TXN, thioredoxin; TXNRD, TXN reductase.

Fig. 3

Proposed mechanism by which supranutritional levels of selenium might suppress the life cycle and mutation to virulence of SARS-COV-2 while attenuating viral-induced oxidative stress, organ damage and the cytokine storm.