Antisense inhibition of selenoprotein synthesis by Zika virus may contribute to neurological disorders and microcephaly by mimicking SePP1 knockout and the genetic disease progressive cerebello-cerebral atrophy

Abstract

Objective: Selenium status plays a major role in health impacts of various RNA viruses. We recently reported potential antisense interactions between viral mRNAs and host mRNAs of the antioxidant selenoprotein thioredoxin reductase (TR). Here, we examine possible targeting of selenoprotein mRNAs by Zika virus (ZIKV) as a pathogenic mechanism, because microcephaly is a key manifestation of Progressive Cerebello-Cerebral Atrophy (PCCA), a genetic disease of impaired selenoprotein synthesis. Methods: Potential antisense matches between ZIKV and human selenoprotein mRNAs were initially identified via nucleotide BLAST searches, using ZIKV genomic RNA as a probe. The strongest antisense matches of ZIKV regions, against human TR1 and selenoprotein P (SePP1), were validated by algorithms for prediction of RNA hybridization and microRNA/target duplexes. The ZIKV-SePP1 interaction was further assessed by gel shift assay. Findings: Computationally, ZIKV has regions of extensive (~30bp) and stable (ΔE < −50kcal/mol) antisense interactions with mRNAs of both TR1 and SePP1, a selenium carrier protein essential for delivery of selenium to the brain. The ZIKV/SePP1 hybridization was experimentally confirmed at the DNA level using synthetic oligonucleotides. Conclusion: Antisense inhibition of TR may be a general RNA virus strategy to favor RNA synthesis over DNA. ZIKV-mediated antisense inhibition of SePP1 and TR1 in fetal brain could mimic SePP1 knockout in mice, contribute to neuronal cell death, and mimic the genetic disease PCCA, characterized by brain atrophy and microcephaly. When given to nursing mothers, sodium selenite can counteract neurological deficits in SePP1 knockout mice, suggesting that a similar approach might help reduce ZIKV-induced human fetal abnormalities.

RNA Viruses vs. DNA Synthesis: A General Viral Strategy That May Contribute to the Protective Antiviral Effects of Selenium

“…As my group first reported in regard to HIV-1 and the Zaire Ebolavirus (EBOV) [17], and later for Zika [18], the possibility that those RNA viruses target thioredoxin reductases (TR) by antisense is supported by computational RNA:RNA hybridization results and preliminary experimental data, in the form of gel shift assays with DNA oligonucleotides. We initially discovered those interaction sites in HIV-1 and EBOV because in both cases they were proximal to highly conserved UGA stop codons (potentially encoding selenocysteine) that terminate the HIV-1 nef and EBOV nucleoprotein open reading frames.…”

“…We have now demonstrated selenium-dependent readthrough of both of those UGA codons, in HIV-1 nef and the EBOV nucleoprotein, and a role for TR1 in the mechanism in the case of nef, via GFP reporter gene assays [20,21]. The fact that in database searches these and other RNA virus mRNAs consistently show a preference for antisense targeting of TR over other viral selenoproteins like GPx supports the supposition that the knockdown of the targeted TR isoforms likely to result from such interactions might also benefit an RNA virus, via the role of TR in DNA synthesis [18]. Figure 1 shows computed RNA secondary structure renditions of these and other virus/human RNA:RNA antisense interactions involving either TR1 or TR3 isoforms.…”

Selenium and RNA Virus Interactions: Potential Implications for SARS-CoV-2 Infection (COVID-19)

“…Although COVID-19 may resemble sepsis, Se potential action in RNA related diseases is quite different (52). Indeed, RNA viruses, including the SARS coronaviruses, likely divert cellular Se for their own selenoproteins (9,33,53,54). Intense viral replication would therefore induce a Se deficiency in the host cell (33,55,56).…”

“…Indeed, RNA viruses, including the SARS coronaviruses, likely divert cellular Se for their own selenoproteins (9,33,53,54). Intense viral replication would therefore induce a Se deficiency in the host cell (33,55,56). In this case, an exogenous supply of Se could restore the host "stock" that is essential for the biosynthesis of cellular selenoproteins, particularly those required for antioxidant defense.…”

“…Taylor and Ruzicka ( 33 ) later presented evidence of similar antisense targeting of several selenoprotein mRNAs, including selenoprotein P and TrxR1, by Zika virus mRNA, and proposed that the antisense knockdown of TrxR isoforms could be a general mechanism by which RNA viruses can increase the pool of ribonucleotides for viral RNA synthesis, by inhibiting the synthesis of DNA ( 33 ). Because of the essential role of TrxR in the thioredoxin system ( 30 ), which is a hydrogen donor for the reduction of ribose to 2'-deoxyribose, they proposed that this could be an effective strategy for RNA viruses.…”