COVID-19: the importance of selenium and glutathione supplementation in order to prevent disease severity


Latest SARS-CoV-2 research conducted by scientist from the Department of Chemistry and Biochemistry at University of North Carolina Greensboro-USA has discovered that the SARS-CoV-2 main protease (Mpro) targets the human host selenoproteins and glutathione biosynthesis for knockdown via proteolysis, potentially disrupting the thioredoxin and glutaredoxin redox cycles.

The study findings were published in the peer reviewed journal: Antioxidants

The risk of continuing emergence of new SARS-CoV-2 variants that can evade our current vaccines and therapeutic monoclonal antibodies [2], along with increasing num- bers of “Long COVID” cases that arise consequent to the ever-expanding cumulative number of COVID-19 survivors [3], highlight a need for complementary therapeutic modalities that can moderate viral pathogenicity via effects on host factors, which are genetically stable compared to viral targets.

Dietary factors including vitamins, minerals, and regulatory molecules like glutathione (GSH) are potentially well suited to this purpose, although their mechanisms, efficacy, and potential utility in the treatment of COVID-19 remain controversial, e.g., in the case of vitamin D, which continues to elicit diametrically opposed claims documented in numerous apparently well conducted studies [4–8].

One of the first micronutrients for which evidence of a significant role in COVID-19 emerged, even within the first months of the pandemic, is the trace element selenium (Se) [9–11]. The fact that multiple research groups from different countries studied this question intensely, almost from the outset of the pandemic, is not that surprising in the light of over 40 years of accumulating evidence that has firmly demonstrated links between Se status and the clinical outcome of various viral infections, including HIV-1, cox- sackieviruses, hepatitis viruses, hantaviruses, influenza virus, and most recently, SARS- CoV-2, as detailed in many recent reviews [12–19].

The sheer number of new review arti- cles on the role of Se in viral infections, and its significance for COVID-19, reflects the greatest rekindling of interest in this topic in several decades.

In all of the reviews cited above, the fundamental roles of the known selenoproteins in various biological processes such as immunity and inflammation has typically been the primary focus; these known mechanisms are then used to explain how Se deficiency in populations may exacerbate viral infections and COVID-19 in particular.

In their reviews, Rayman and coworkers have gone somewhat deeper, also considering the potential importance of (1) direct antiviral roles of low molecular weight redox-active Se species, and (2) the possibility that some viruses, and SARS-CoV-2 specifically, employ mechanisms designed to obstruct critical selenoprotein mediated defense mechanisms via active suppression of selenoprotein gene expression, potentially at both the RNA and protein levels [14,19].

The importance of Se for the immune response was already emerging in the late 1970s [20], and by the 1990s, it was well understood to be an essential nutrient for immune func- tion, as well as for antioxidant defenses and cellular survival [21–23]. This decades-old foundational understanding has now been greatly expanded by the discovery of additional human selenoproteins and their roles in the immune system [24,25].

This knowledge has tended to favor a mindset that sub-par expression of specific selenoproteins leading to impaired immunity is the major basis of links between Se and viral pathology, which hence are fundamentally a problem limited to Se deficient populations, and possibly those with comorbidities that might impair selenoprotein function.

This model as applied to SARS-CoV-2 is typified by Figure 2 in the review by Bermano et al. [12]. However, if it is true that inadequate levels of critical selenoproteins undermine immunity and other essential host processes, thereby enhancing vulnerability to viral pathogenesis, then it should be equally true that a virus could benefit by actively suppressing the levels of those same selenoproteins.

If so, individuals with adequate dietary intake but high viral loads might be suffering from impaired selenoprotein function due to viral knockdown, and thus potentially might benefit from increased supra- nutritional intake of Se.

Based on further analysis of the data from Zhang et al., correlating Se status (based upon hair analysis) with COVID-19 recovery rates in Chinese cities [9], Figure 1 of Ray- man et al. [19] suggests that, indeed, there is a protective effect of Se dietary intakes at levels that exceed those previously shown to be sufficient to optimize the expression of critical selenoproteins like glutathione peroxidase 1 (GPX1) and selenoprotein P (SelenoP).

This implies that there is more going on with Se in COVID-19 than simply the rectification of a dietary deficiency.
Furthermore, in an analysis of the effects of SARS infection on expression of seleno-protein mRNAs in Vero cells, Wang et al. reported that six of the 25 known selenoproteins mRNAs were significantly suppressed in infected cells [26]. In the case of thioredoxin re- ductase 3 (TXNRD3), evidence was also presented consistent with the possibility of an antisense interaction between the selenoprotein mRNA and the viral mRNA as a possible mechanism of mRNA suppression.

These results strongly support the hypothesis that SARS-CoV-2 is actively engaged in the mRNA suppression-based knockdown of a number of host selenoproteins, including glutathione peroxidase 4 (GPX4), TXNRD3, and four endoplasmic reticulum (ER)-resident selenoproteins [26].

Evidence for a possible active selenoprotein knockdown strategy by SARS-CoV-2 at the protein level was presented by Taylor and Radding [27]. Using web server-based computational methods, we identified short protein sequences in a handful of host proteins that closely match the known target sequences of the SARS-CoV-2 main protease (Mpro, also called the 3CL protease).

Candidate Mpro cleavage sites were identified in four sele- noproteins: selenoprotein F (SelenoF), SelenoP, GPX1, and thioredoxin reductase 1 (TXNRD1), as well as in two conventional proteins: glutaredoxin (GLRX-1) and the cata- lytic subunit of γ-glutamate cysteine ligase (GCLC), the rate-limiting enzyme for GSH syn- thesis.

Further examination using available 3D structures suggested that all of these po- tential Mpro cleavage sites are close to the protein surface where they would be accessible to the viral protease, as shown in Figure S3 of reference [27].

It should be noted that other confirmed and unconfirmed cellular targets of SARS- CoV-2 proteases, both Mpro and the viral “papain-like protease” (PLpro), have been identified [28–31]. Experimentally confirmed Mpro targets include three proteins involved in host innate immune responses: NLR Family Pyrin Domain Containing 12 (NLRP12), In- terleukin-1 Receptor-Associated Kinase 1 (IRAK1), and TGF-Beta Activated Kinase 1 (TAB1), and in addition, C-Terminal-Binding Protein 1 (CTBP1), a protein involved in control of cell development, oncogenesis, and apoptosis [29,30].

The primary function of viral proteases is for virion maturation via viral polyprotein processing, to form the functional structural components of the virion, as well as viral enzymes and regulatory proteins. However, it is also well established that some viral proteases have coevolved to additionally target specific host proteins, whose knockdown may facilitate some aspects of viral replication or pathogenesis, e.g., as reviewed by Blanco et al. in the case of HIV-1, as just one example [32]. In the case of GSH biosynthesis and the selenoprotein TXNRD1 as potential viral protease targets [27], there is a clear rationale as to how their knockdown would assist the replication of an RNA virus like SARS-CoV-2.

By interfering with the two essential redox cycles needed to sustain the action of ribonucleotide reductase, proteolytic knockdown of both TXNRD1 and GCLC is consistent with a viral strategy to inhibit DNA synthesis, to conserve the pool of ribonucleotides for increased virion production [33]. This hypothesis will be examined in detail in Section 4.

Thus, the principal aim of this work was to experimentally assess the functionality of the potential Mpro cleavage sites in the six host proteins identified previously, listed in Figure 2 of Taylor and Radding [27], and in simplified format here in Figure 1. Cleavage was assessed under buffered cell-free conditions, by incubating recombinant SARS-CoV- 2 Mpro with synthetic peptides spanning the proposed cleavage sites, and analyzing the products via UPLC-MS.

Our results showed that the predicted cleavage site candidates in four of the six proteins actually function as Mpro substrates. Because the predicted cleavage site in TXNRD1 is right at the protein C-terminus, and is expected to generate a five-residue P′ fragment that includes the essential C-terminal redox center of thioredoxin reductase, we were also able to demonstrate this cleavage from a full 499-residue TXNRD1 protein, under similar cell-free conditions.

For this purpose, SARS-CoV-2 Mpro was incubated with a recombinant Sec498Ser mutant of the TXNRD1 protein, which generated the same five-residue peptide P′ fragment as the decamer shown for TXNRD1 in Figure 1.

FIGURE 1. Coronavirus Mpro cleavage site consensus sequence logo plots and comparisons. Logo plots from multiple alignments of the known Mpro cleavage sites are shown for the 2003 SCoV (A) and 2019 SCoV2 (B). The height of a letter at each position reflects its probability in the alignment; each of the logos shown represents the consensus of 11 Mpro cleavage sites from a single virus. Plots were generated using WebLogo (, from the alignments in Figure S1(C) Comparison of the GPX1 active site sequence containing selenocysteine (U) to the known SCoV2 Mpro cleavage site at the nsp13/14 junction; this site is identical in the 2003 and 2019 coronaviruses. (D) Comparison of a predicted Mpro cleavage site in human selenoprotein F to a known SCoV2 Mpro cleavage site at the nsp12/13 junction.

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