Integrative Analysis of Zika Virus Genome RNA Structure Reveals Critical Determinants of Viral Infectivity

SUMMARYSince its outbreak in 2007, Zika virus (ZIKV) has become a global health threat that causes severe neurological conditions. Here we perform a comparativein vivostructural analysis of the RNA genomes of two ZIKV strains to decipher the regulation of their infection at the RNA level. Our analysis identified both known and novel functional RNA structural elements. We discovered a functional long-range intramolecular interaction specific for the Asian epidemic strains, which contributes to their infectivity. Our findings illuminate the structural basis of ZIKV regulation and provide a rich resource for the discovery of RNA structural elements that are important for ZIKV infection.

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Evaluation of Conserved RNA Secondary Structures within and between Geographic Lineages of Zika Virus

Life ◽

10.3390/life11040344 ◽

2021 ◽

Vol 11 (4) ◽

pp. 344

Author(s):

Kevin Nicolas Calderon ◽

Johan Fabian Galindo ◽

Clara Isabel Bermudez-Santana

Keyword(s):

Zika Virus ◽

Rna Structure ◽

Potential Role ◽

Genome Structure ◽

Nucleotide Substitutions ◽

Genomic Comparison ◽

Genome Variability ◽

Vital Functions ◽

Host Cell Interactions ◽

Rna Genome

Zika virus (ZIKV), without a vaccine or an effective treatment approved to date, has globally spread in the last century. The infection caused by ZIKV in humans has changed progressively from mild to subclinical in recent years, causing epidemics with greater infectivity, tropism towards new tissues and other related symptoms as a product of various emergent ZIKV–host cell interactions. However, it is still unknown why or how the RNA genome structure impacts those interactions in differential evolutionary origin strains. Moreover, the genomic comparison of ZIKV strains from the sequence-based phylogenetic analysis is well known, but differences from RNA structure comparisons have barely been studied. Thus, in order to understand the RNA genome variability of lineages of various geographic distributions better, 410 complete genomes in a phylogenomic scanning were used to study the conservation of structured RNAs. Our results show the contemporary landscape of conserved structured regions with unique conserved structured regions in clades or in lineages within circulating ZIKV strains. We propose these structures as candidates for further experimental validation to establish their potential role in vital functions of the viral cycle of ZIKV and their possible associations with the singularities of different outbreaks that lead to ZIKV populations to acquire nucleotide substitutions, which is evidence of the local structure genome differentiation.

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Activation of viral transcription by stepwise largescale folding of an RNA virus genome

Nucleic Acids Research ◽

10.1093/nar/gkaa675 ◽

2020 ◽

Vol 48 (16) ◽

pp. 9285-9300

Author(s):

Tamari Chkuaseli ◽

K Andrew White

Keyword(s):

Rna Structure ◽

Rna Viruses ◽

Rna Virus ◽

Initial Step ◽

Binding Pocket ◽

Regulatory Elements ◽

Virus Genome ◽

Genomic Rna ◽

Stem Loop ◽

Rna Complex

Abstract The genomes of RNA viruses contain regulatory elements of varying complexity. Many plus-strand RNA viruses employ largescale intra-genomic RNA-RNA interactions as a means to control viral processes. Here, we describe an elaborate RNA structure formed by multiple distant regions in a tombusvirus genome that activates transcription of a viral subgenomic mRNA. The initial step in assembly of this intramolecular RNA complex involves the folding of a large viral RNA domain, which generates a discontinuous binding pocket. Next, a distally-located protracted stem-loop RNA structure docks, via base-pairing, into the binding site and acts as a linchpin that stabilizes the RNA complex and activates transcription. A multi-step RNA folding pathway is proposed in which rate-limiting steps contribute to a delay in transcription of the capsid protein-encoding viral subgenomic mRNA. This study provides an exceptional example of the complexity of genome-scale viral regulation and offers new insights into the assembly schemes utilized by large intra-genomic RNA structures.

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Genome-wide Integrative Analysis of Zika-Virus-Infected Neuronal Stem Cells Reveals Roles for MicroRNAs in Cell Cycle and Stemness

Cell Reports ◽

10.1016/j.celrep.2019.05.059 ◽

2019 ◽

Vol 27 (12) ◽

pp. 3618-3628.e5 ◽

Cited By ~ 15

Author(s):

Jason W. Dang ◽

Shashi Kant Tiwari ◽

Yue Qin ◽

Tariq M. Rana

Keyword(s):

Cell Cycle ◽

Stem Cells ◽

Zika Virus ◽

Integrative Analysis ◽

Neuronal Stem Cells ◽

Genome Wide

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CpG-Recoding in Zika Virus Genome Causes Host-Age-Dependent Attenuation of Infection With Protection Against Lethal Heterologous Challenge in Mice

Frontiers in Immunology ◽

10.3389/fimmu.2019.03077 ◽

2020 ◽

Vol 10 ◽

Cited By ~ 8

Author(s):

Ivan Trus ◽

Daniel Udenze ◽

Nathalie Berube ◽

Colette Wheler ◽

Marie-Jocelyne Martel ◽

...

Keyword(s):

Zika Virus ◽

Virus Genome ◽

Host Age ◽

Heterologous Challenge ◽

Age Dependent

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Zika virus genome biology and molecular pathogenesis

Emerging Microbes & Infections ◽

10.1038/emi.2016.141 ◽

2017 ◽

Vol 6 (1) ◽

pp. 1-6 ◽

Cited By ~ 42

Author(s):

Anyou Wang ◽

Stephanie Thurmond ◽

Leonel Islas ◽

Kingyung Hui ◽

Rong Hai

Keyword(s):

Zika Virus ◽

Virus Genome ◽

Genome Biology ◽

Molecular Pathogenesis

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Zika virus genome from the Americas

The Lancet ◽

10.1016/s0140-6736(16)00003-9 ◽

2016 ◽

Vol 387 (10015) ◽

pp. 227-228 ◽

Cited By ~ 165

Author(s):

Antoine Enfissi ◽

John Codrington ◽

Jimmy Roosblad ◽

Mirdad Kazanji ◽

Dominique Rousset

Keyword(s):

Zika Virus ◽

Virus Genome

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The translational landscape of Zika virus during infection of mammalian and insect cells

10.1101/112904 ◽

2017 ◽

Cited By ~ 1

Author(s):

Nerea Irigoyen ◽

Adam M. Dinan ◽

Luke W. Meredith ◽

Ian Goodfellow ◽

Ian Brierley ◽

...

Keyword(s):

Zika Virus ◽

Insect Cells ◽

Rna Virus ◽

Neurological Complications ◽

Virus Genome ◽

Ribosome Profiling ◽

Western Hemisphere ◽

Open Reading Frames ◽

Rapid Expansion ◽

Congenital Diseases

AbstractZika virus is a single-stranded, positive-sense RNA virus of the family Flaviviridae, which has recently undergone a rapid expansion among humans in the Western Hemisphere. Here, we report a high-resolution map of ribosomal occupancy of the Zika virus genome during infection of mammalian and insect cells, obtained by ribosome profiling. In contrast to some other flaviviruses such as West Nile, we find no evidence for substantial frameshift-induced ribosomal drop-off during translation of the viral polyprotein, indicating that Zika virus must use alternative mechanisms to downregulate levels of catalytically active viral polymerase. We also show that high levels of ribosome-protected fragments map in-frame to two previously overlooked upstream open reading frames (uORFs) initiating at CUG and UUG codons, with likely consequences for the efficiency of polyprotein expression. Curiously, in African isolates of Zika virus, the two uORFs are fused in-frame into a single uORF. A parallel RNA-Seq analysis reveals the 5′ end position of the subgenomic flavivirus RNA in mammalian and insect cells. Together, these provide the first analysis of flavivirus gene expression by ribosome profiling.Author SummaryRecent Zika virus outbreaks have been associated with congenital diseases and neurological complications. An enhanced understanding of the molecular biology of this pathogen may contribute towards the development of improved treatment and control methods. We present a single-codon resolution analysis of Zika virus translation in mammalian and mosquito cells using ribosome profiling. The analysis revealed two hitherto uncharacterized uORFs in the 5′ leader of Zika virus Brazilian isolate PE243, both of which are occupied by ribosomes during infection. In contrast, these two uORFs are fused into a single uORF in African isolates. This observation provides a new avenue for further investigations into potential factors involved in the emergence of Zika virus from a rarely detected pathogen into a major epidemic.

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Clustering of Zika viruses originating from different geographical regions using computational sequence descriptors

Current Computer - Aided Drug Design ◽

10.2174/1573409916666191226110936 ◽

2019 ◽

Vol 16 ◽

Author(s):

Marjan Vračko ◽

Subhash C. Basak ◽

Dwaipayan Sen ◽

Ashesh Nandy

Keyword(s):

Zika Virus ◽

Virus Genome ◽

Host Cells ◽

Genome Sequences ◽

Region Of Origin ◽

Self Organizing Maps ◽

Data Set ◽

Mahalanobis Distances ◽

Geographical Regions ◽

Self Organizing

: In this report we consider a data set, which consists of 310 Zika virus genome sequences taken from different continents, Africa, Asia and South America. The sequences, which were compiled from GenBank, were derived from the host cells of different mammalian species (Simiiformes, Aedes opok, Aedes africanus, Aedes luteocephalus, Aedes dalzieli, Aedes aegypti, and Homo sapiens). For chemometrical treatment the sequences have been represented by sequence descriptors derived from their graphs or neighborhood matrices. The set was analyzed with three chemometrical methods: Mahalanobis distances, principal component analysis (PCA) and self organizing maps (SOM). A good separation of samples with respect to the region of origin was observed using these three methods. Background: Study of 310 Zika virus genome sequences from different continents. Objective: To characterize and compare Zika virus sequences from around the world using alignment-free sequence comparison and chemometrical methods. Method: Mahalanobis distance analysis, self organizing maps, principal components were used to carry out the chemometrical analyses of the Zika sequence data. Results: Genome sequences are clustered with respect to the region of origin (continent, country) Conclusion: Africa samples are well separated from Asian and South American ones.

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The Nucleotides on the Stem-Loop RNA Structure in the Junction Region of the Hepatitis E Virus Genome Are Critical for Virus Replication

Journal of Virology ◽

10.1128/jvi.01475-10 ◽

2010 ◽

Vol 84 (24) ◽

pp. 13040-13044 ◽

Cited By ~ 48

Author(s):

Dianjun Cao ◽

Yao-Wei Huang ◽

Xiang-Jin Meng

Keyword(s):

Virus Replication ◽

Intergenic Region ◽

Rna Structure ◽

Hepatitis E Virus ◽

Reporter Genes ◽

Hepatitis E ◽

Virus Genome ◽

Junction Region ◽

Stem Loop ◽

Huh7 Cells

ABSTRACT The roles of conserved nucleotides on the stem-loop (SL) structure in the intergenic region of the hepatitis E virus (HEV) genome in virus replication were determined by using Huh7 cells transfected with HEV SL mutant replicons containing reporter genes. One or two nucleotide mutations of the AGA motif on the loop significantly reduced HEV replication, and three or more nucleotide mutations on the loop abolished HEV replication. Mutations on the stem and of the subgenome start sequence also significantly inhibited HEV replication. The results indicated that both the sequence and the SL structure in the junction region play important roles in HEV replication.

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