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Explaining Flavivirus Congenital Neurotropism with Thermodynamics

July 2018

DOI:10.13140/RG.2.2.19047.14244

Conference: Computational Approaches to RNA Structure and Function 2018

Authors:

Michael T. Wolfinger

RNA Forecast

Flaviviruses represent a global health threat and are responsible for millions of infections in humans every year. During the 2015-2017 outbreak of Zika virus (ZIKV) in the Americas accumulation of congenital microcephaly cases was observed, which has been associated with ZIKV infection. However, the underlying biological mechanisms remain elusive. Recently, experimental studies showed that the host protein Musashi-1 (Msi1) mediates ZIKV replication. Msi1, which is expressed in neuronal progenitor cells and tumors, typically binds single-standed UAG motifs in the 3'UTR of RNA. Here we employ a biophysical model of RNA structure formation to show that UAGs within ZIKV 3'UTRs are highly accessible and therefore represent optimal Msi1 binding targets. More generally, the theoretical approach presented here allows to predict the Msi-mediated teratogenic potential of related arboviruses.

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Preprint

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Musashi binding elements in Zika and related Flavivirus 3'UTRs: A comparative study in silico

September 2018

Zika virus (ZIKV) belongs to a class of neurotropic viruses that have the ability to cause congenital infection, which can result in microcephaly or fetal demise. Recently, the RNA-binding protein Musashi-1 (Msi1), which mediates the maintenance and self-renewal of stem cells and acts as a translational regulator, has been associated with promoting ZIKV replication, neurotropism, and pathology. ... [Show full abstract] Msi1 predominantly binds to single-stranded UAG motifs in the 3'UTR of RNA. We systematically analyzed the properties of Musashi binding elements (MBEs) in the 3'UTR of flaviviruses based on a thermodynamic model for RNA folding. Our results indicate that MBEs in ZIKV 3'UTRs occur predominantly in unpaired, single-stranded structural context, thus corroborating experimental observations by a biophysical model of RNA structure formation. Statistical analysis and comparison with related viruses shows that ZIKV MBEs are maximally accessible among all mosquito-borne flaviviruses. Our study addresses the broader question whether other emerging arboviruses can cause similar neurotropic effects through the same mechanism in the developing fetus. In this line, we establish a link between the biophysical properties of viral RNA and teratogenicity. Moreover, our thermodynamic model can explain recent experimental findings and predict the Msi1-related neurotropic potential of other viruses.

Poster

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Musashi Binding Elements in Zika and Related Flavivirus 3'UTRs

June 2018

Emerging and re-emerging arthropod-borne viruses such as Japanese encephalitis (JEV), Dengue (DENV), Yellow fever (YFV), and Chikungunya (CHIKV) viruses are a growing global health threat. Zika virus (ZIKV) is a neurotropic flavivirus (FV) that can cause congenital infection, which can result in microcephaly and fetal demise. Recently, the translational regulator protein Musashi-1 (Msi1) has been ... [Show full abstract] attributed to promoting ZIKV replication, neurotropism, and pathology. Msi1 predominantly binds single-stranded UAG motifs in the 3'UTR of RNA. 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 affinity with a thermodynamic model of RNA structure formation.

Article

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Musashi binding elements in Zika and related Flavivirus 3′UTRs: A comparative study in silico

May 2019 · Scientific Reports

Zika virus (ZIKV) belongs to a class of neurotropic viruses that have the ability to cause congenital infection, which can result in microcephaly or fetal demise. Recently, the RNA-binding protein Musashi-1 (Msi1), which mediates the maintenance and self-renewal of stem cells and acts as a translational regulator, has been associated with promoting ZIKV replication, neurotropism, and pathology. ... [Show full abstract] Msi1 predominantly binds to single-stranded motifs in the 3′ untranslated region (UTR) of RNA that contain a UAG trinucleotide in their core. We systematically analyzed the properties of Musashi binding elements (MBEs) in the 3′UTR of flaviviruses with a thermodynamic model for RNA folding. Our results indicate that MBEs in ZIKV 3′UtRs occur predominantly in unpaired, single-stranded structural context, thus corroborating experimental observations by a biophysical model of RNA structure formation. statistical analysis and comparison with related viruses show that ZIKV MBEs are maximally accessible among mosquito-borne flaviviruses. Our study addresses the broader question of whether other emerging arboviruses can cause similar neurotropic effects through the same mechanism in the developing fetus by establishing a link between the biophysical properties of viral RNA and teratogenicity. Moreover, our thermodynamic model can explain recent experimental findings and predict the Msi1-related neurotropic potential of other viruses.

Presentation

Full-text available

The quest for conserved RNAs in viral genomes

October 2019

Michael T. Wolfinger

Arthropod-borne RNA viruses (arboviruses) represent a global health threat, causing millions of human and animal infections every year. Recent outbreaks of emerging and re-emerging viruses have revealed new clinical manifestations, e.g., the accumulation of congenital microcephaly cases during the Zika virus epidemic in the Americas 2015-2016. While vaccines against many of these viruses are ... [Show full abstract] still under development, experimental data suggest an involvement of RNA structure in viral pathogenesis. Comparative studies of RNA structure combine thermodynamic modeling, phylogenomics and homology search, thereby providing a powerful approach for characterizing the evolutionary conservation of viral genomes. In particular, untranslated regions (UTRs) of arboviruses harbor functional RNA elements, which play vital roles in virus replication and often mediate tropism. Here, the availability of large amounts of genome data allows building fine-grained models of homologous RNA structures in phylogenetically related viruses. On a broader scale, these data reveal common patterns and evolutionary traits of non-coding viral RNAs.