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The Role of Arbovirus UTRs on Neurotropism

Authors:

Abstract

Purpose: Arboviruses are a group of viruses transmitted by arthropods, mostly ticks, and mosquitoes. Among the members of this group are the families Togaviridae and Flaviviridae, (+)ssRNA viruses, such as Chikungunya, Dengue, and Zika. Multiple of these viruses have demonstrated their ability to cause neuropathology in humans. In Zika, a protein binding motif known as Musashi binding element (MBE) has been attributed to promoting replication, neurotropism, and pathology. Musashi-1 (MSI1) is an RNA-binding protein involved in the maintenance and self-renewal of stem cells and a translational regulator in many biological systems. MSI1 predominantly binds single-stranded UAG motifs in the 3’ untranslated region (UTR) of RNA. We have recently analyzed Musashi binding elements (MBEs) in the 3’UTR of flaviviruses in silico. In this study, we could show that MBEs in the 3’UTR of neurotropic viruses such as Zika, West Nile, and Powassan virus are highly accessible, and mostly occur in an unpaired structural context, which renders them optimal Musashi binding targets and corroborates previous experimental studies by a theoretical model. Methods & Materials: To expand to other related viruses, we systematically analyzed the properties of Musashi binding elements (MBEs) in the 3’UTR of alphaviruses based on a thermodynamic model for RNA folding and correlated to the currently described pathogenicity in literature. Results: Our results indicate that MBEs in the 3’UTR of alphaviruses are not as accessible as in flaviviruses, suggesting that the MBE role in neuropathology might be an exclusive feature of flaviviruses. Conclusion: Our study addresses the broader question whether other emerging arboviruses can cause similar neurotropic effects. We expanded our study from an initial flavivirus dataset to all (+)ssRNA flavi- and alphaviruses to evaluate the link between MBE accessibility and currently described neuropathology. Moreover, our thermodynamic model can be the initial indicative for in vivo studies to evaluate the potential neurotropic effect of MBEs on different viral families.
The Role of Arbovirus UTRs on Neurotropism
Adriano de Bernardi Schneider3 and Michael T. Wolnger1,2
1Department of Theoretical Chemistry, University of Vienna, Währingerstraße 17, 1090 Vienna, Austria
2Center for Anatomy and Cell Biology, Medical University of Vienna, Währingerstraße 13, 1090 Vienna, Austria
3Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, North Carolina, USA
[1] Chavali, P.L. et al. (2017), Neurodevelopmental protein Musashi 1 interacts with the Zika genome and promotes viral replication, Science, eaam92433
[2] Uren, P.J. et al. (2015), RNA-binding protein Musashi1 is a central regulator of adhesion pathways in glioblastoma, Mol Cell Biol, 35.17, 2965-2978
[3] Lorenz, R. et al. (2011), ViennaRNA Package 2.0, Algorithm Mol Biol 6:1, 26
[4] Zearfoss, N.R. et al. (2014), A conserved three-nucleotide core motif denes Musashi RNA binding specicity, J Biol Chem 289(51):35530-35541
[5] Platt, D.J. et al. (2018), Zika virus-related neurotropic aviviruses infect human placental explants and cause fetal demise in mice, Sci Transl Med, 10(426) eaao7090
[6] de Bernardi Schneider, A. et al. (2018) Musashi binding elements in Zika and related Flavivirus 3'UTRs: A comparative study in silico, bioRxiv 407833
Contact: michael.wolnger@univie.ac.at - http://www.tbi.univie.ac.at/~mtw
1. Background and outline
3. Opening energy and single-strandedness
5. MBE accessibility in the 3'UTR of aviviruses and alphaviruses
Acknowledgements: This work was partly funded by the Austrian Science Fund FWF project F43.
Emerging and re-emerging arthropod-borne viruses such as Japanese
encephalitis (JEV), Dengue (DENV), Yellow fever (YFV), and Chikun-
gunya (CHIKV) viruses are a growing global health threat. Zika virus
(ZIKV) is a neurotropic avivirus (FV) that can cause congenital
infection, which can result in microcephaly and fetal demise.
Recently, the translational regulator protein Musashi-1 (Msi1) has
been attributed to promoting ZIKV replication, neurotropism,
and pathology [1]. Msi1 predominantly binds single-stranded UAG
motifs in the 3'UTR of RNA [2].
Here we systematically analyzed the thermodynamic properties of
Musashi binding elements (MBEs) in the 3'UTR of 76 arbovirus
genomes in silico. Our results indicate that MBEs in the ZIKV 3'UTR
occur predominantly in unpaired, single-stranded structural context,
thus supporting experimental observations of Msi1 binding
anity with a thermodynamic model of RNA structure formation.
We use the ViennaRNA Package [3] to model the thermodynamics
of RNA secondary structure formation. The partition function allows
for computation of the equilibrium probability of secondary structure
4. MBE accessibility in ZIKV 3'UTR
Fig 3. Distribution of MBE opening energy scores in avivirus 3'UTRs. Colors indicate sercomplexes (ISFV: Insect-specic
aviviruses; MBFV: Mosquito-borne aviviruses; NKV: No known vector aviviruses; TBFV: Tick-borne aviviruses). Only
viruses with more than two MBEs within the 3'UTR shown.
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Musashi binding elements in Zika and related Flavivirus 3'UTRs: A comparative study in silico, bioRxiv 407833 Contact: michael.wolfinger@univie.ac
  • De Bernardi
  • A Schneider
de Bernardi Schneider, A. et al. (2018) Musashi binding elements in Zika and related Flavivirus 3'UTRs: A comparative study in silico, bioRxiv 407833 Contact: michael.wolfinger@univie.ac.at-http://www.tbi.univie.ac.at/~mtw