The role of Arbovirus genome untranslated regions on neurotropism

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 (FV) 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: In order to expand to other related viruses, we systematically analyzed the properties of Musashi binding elements (MBEs) in the 3’UTR of Alphaviruses (AV) based on a thermodynamic model for RNA folding and correlated to the currently described pathogenicity in literature. Results: Our preliminary results indicate that MBEs in the 3’UTR of Chikungunya, Venezuelan Equine Encephalitis, and Eastern Equine Encephalitis viruses occur predominantly in paired, double-stranded structural context, suggesting that the mechanism to cause neurotropism in these AV must be a different one. Analyses in other AV are currently being performed to investigate the role of MBEs in a more broad dataset. Our initial analysis suggests that the MBE role in neuropathology may be an exclusive feature of FV. Conclusion: Our study addresses the broader question whether other emerging arboviruses can cause similar neurotropic effects. We expanded our study from a previous Flavivirus dataset to all (+)ssRNA arboviruses to evaluate the link between MBE 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.