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The quest for conserved RNAs in viral genomes



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 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.
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Chikungunya virus (CHIKV), a mosquito-borne alphavirus of the family Togaviridae, has recently emerged in the Americas from lineages from two continents: Asia and Africa. Historically, CHIKV circulated as at least four lineages worldwide with both enzootic and epidemic transmission cycles. To understand the recent patterns of emergence and the current status of the CHIKV spread, updated analyses of the viral genetic data and metadata are needed. Here, we performed phylogenetic and comparative genomics screens of CHIKV genomes, taking advantage of the public availability of many recently sequenced isolates. Based on these new data and analyses, we derive a revised phylogeny from nucleotide sequences in coding regions. Using this phylogeny, we uncover the presence of several distinct lineages in Africa that were previously considered a single one. In parallel, we performed thermodynamic modeling of CHIKV untranslated regions (UTRs), which revealed evolutionarily conserved structured and unstructured RNA elements in the 3'UTR. We provide evidence for duplication events in recently emerged American isolates of the Asian CHIKV lineage and propose the existence of a flexible 3'UTR architecture among different CHIKV lineages.
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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. 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.
• FV include (re-)emerging human pathogens like YFV
  • Wnv Tbev
• FV include (re-)emerging human pathogens like YFV, DENV, JEV, WNV, TBEV
• Congenital neurotropism: high increase in microcephaly cases in newborns Weaver and Forrester
• Congenital neurotropism: high increase in microcephaly cases in newborns Weaver and Forrester, Antivir. Res. (2015) and Forrester, Antivir. Res. (2015)
  • Forrester Weaver
Weaver and Forrester, Antivir. Res. (2015)