SARS-CoV-2 suppresses mRNA expression of selenoproteins associated with ferroptosis, endoplasmic reticulum stress and DNA synthesis

Abstract

Higher selenium status has been shown to improve the clinical outcome of infections caused by a range of evolutionally diverse viruses, including SARS-CoV-2. However, the impact of SARS-CoV-2 on host-cell selenoproteins remains elusive. The present study investigated the influence of SARS-CoV-2 on expression of selenoprotein mRNAs in Vero cells. SARS-CoV-2 triggered an inflammatory response as evidenced by increased IL-6 expression. Of the 25 selenoproteins, SARS-CoV-2 significantly suppressed mRNA expression of ferroptosis-associated GPX4, DNA synthesis-related TXNRD3 and endoplasmic reticulum-resident SELENOF, SELENOK, SELENOM and SELENOS. Computational analysis has predicted an antisense interaction between SARS-CoV-2 and TXNRD3 mRNA, which is translated with high efficiency in the lung. Here, we confirmed the predicted SARS-CoV-2/ TXNRD3 antisense interaction in vitro using DNA oligonucleotides, providing a plausible mechanism for the observed mRNA knockdown. Inhibition of TXNRD decreases DNA synthesis which is thereby likely to increase the ribonucleotide pool for RNA synthesis and, accordingly, RNA virus production. The present findings provide evidence for a direct inhibitory effect of SARS-CoV-2 replication on the expression of a specific set of selenoprotein mRNAs, which merits further investigation in the light of established evidence for correlations between dietary selenium status and the outcome of SARS-CoV-2 infection.

The Relevance of Plant-Derived Se Compounds to Human Health in the SARS-CoV-2 (COVID-19) Pandemic Era

“…In Enshi, which is one of the areas in the world where the local population has the highest Se intake in the diet, the recovery rate from COVID-19 was almost triple the average for the other cities in Hubei Province [129]. Additionally, other very recent studies provide evidence of a potential link between SARS-CoV-2 inflammation and the Se status, as infected cells in culture contained reduced amounts of selenoproteins and concurrently developed the production of factors (e.g., cytokines) that deplete their biosynthesis [126]. In particular, increased expression of IL-6, an inflammatory cytokine positively correlated with the severity of SARS-CoV-2 [126], was reported to decline the concentration of SelP and expression of deiodinase type 1 (DIO1) [130].…”

“…Additionally, other very recent studies provide evidence of a potential link between SARS-CoV-2 inflammation and the Se status, as infected cells in culture contained reduced amounts of selenoproteins and concurrently developed the production of factors (e.g., cytokines) that deplete their biosynthesis [126]. In particular, increased expression of IL-6, an inflammatory cytokine positively correlated with the severity of SARS-CoV-2 [126], was reported to decline the concentration of SelP and expression of deiodinase type 1 (DIO1) [130]. Hypercytokinemia (i.e., high levels of cytokinins) observed in hosts affected by severe SARS-CoV-2 infection is responsible for inducing damage to the lung epithelium cells that can promote the occurrence of further infections, either bacterial or fungal [12].…”

“…Among selenoproteins, it is worth mentioning glutathione peroxidases (GPx1, GPx2, GPx3, and GPx 4), thioredoxin reductases (TXNRD1, TXNRD2, and TXNRD3), methionine sulfoxide reductase B1 (MSRB1), selenoprotein P, selenoprotein K, selenoprotein W, peroxisome proliferator-activated nuclear receptor-γ, and IκB-kinase β ([10], references therein). Such proteins can act through different mechanisms for counteracting pathogens [126]. For instance, they display antioxidant (e.g., GPx and TXNRD), redox (e.g., TXNRD), anti-inflammatory (e.g., GPXs, TXNRDs, and selenoprotein S), and immune functions (e.g., GPxs, TXNRDs, MSRB1, selenoprotein K, and selenoprotein S) [126].…”

“…Such proteins can act through different mechanisms for counteracting pathogens [126]. For instance, they display antioxidant (e.g., GPx and TXNRD), redox (e.g., TXNRD), anti-inflammatory (e.g., GPXs, TXNRDs, and selenoprotein S), and immune functions (e.g., GPxs, TXNRDs, MSRB1, selenoprotein K, and selenoprotein S) [126].…”

“…SARS-CoV-2 also overwhelms the transcription of selenoproteins associated with ferroptosis (GPx4), endoplasmic reticulum (ER), stress (selenoprotein F, selenoprotein K, selenoprotein M, and selenoprotein S), and DNA synthesis (thioredoxin reductase 3) [126]. The decrease in ER-associated selenoproteins can cause protein misfolding and enhance ER stress, with detrimental outcomes in cells [126,131].…”