Antisense inhibition of selenoprotein synthesis by Zika virus may contribute to neurological disorders and microcephaly by mimicking SePP1 knockout and the genetic disease PCCA
- UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
- Ethan W Taylor, Senior Research Professor (Creator)
- Institution
- The University of North Carolina at Greensboro (UNCG )
- Web Site: http://library.uncg.edu/
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 (?E < -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.
Antisense inhibition of selenoprotein synthesis by Zika virus may contribute to neurological disorders and microcephaly by mimicking SePP1 knockout and the genetic disease PCCA
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Additional Information
- Publication
- Bulletin of the World Health Organization. E-pub: 13 July 2016. doi: http://dx.doi.org/10.2471/BLT.16.182071
- Language: English
- Date: 2016
- Keywords
- Zika virus, selenium, antisense inhibition, selenoprotein