Deep Sequencing Identifies Noncanonical Editing of Ebola and Marburg Virus RNAs in Infected Cells

ABSTRACT Deep sequencing of RNAs produced by Zaire ebolavirus (EBOV) or the Angola strain of Marburgvirus (MARV-Ang) identified novel viral and cellular mechanisms that diversify the coding and noncoding sequences of viral mRNAs and genomic RNAs. We identified previously undescribed sites within the EBOV and MARV-Ang mRNAs where apparent cotranscriptional editing has resulted in the addition of non-template-encoded residues within the EBOV glycoprotein (GP) mRNA, the MARV-Ang nucleoprotein (NP) mRNA, and the MARV-Ang polymerase (L) mRNA, such that novel viral translation products could be produced. Further, we found that the well-characterized EBOV GP mRNA editing site is modified at a high frequency during viral genome RNA replication. Additionally, editing hot spots representing sites of apparent adenosine deaminase activity were found in the MARV-Ang NP 3′-untranslated region. These studies identify novel filovirus-host interactions and reveal production of a greater diversity of filoviral gene products than was previously appreciated. IMPORTANCE This study identifies novel mechanisms that alter the protein coding capacities of Ebola and Marburg virus mRNAs. Therefore, filovirus gene expression is more complex and diverse than previously recognized. These observations suggest new directions in understanding the regulation of filovirus gene expression. This study identifies novel mechanisms that alter the protein coding capacities of Ebola and Marburg virus mRNAs. Therefore, filovirus gene expression is more complex and diverse than previously recognized. These observations suggest new directions in understanding the regulation of filovirus gene expression.

• Publication year

  2014

• Venue

  mBio

• Publication date

  2014-11-04

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1128/mBio.02011-14PMID 25370495PMCID 4222107
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Comprehensive Functional Analysis of N-Linked Glycans on Ebola Virus GP1

  2014cited by this paper
• Ebola haemorrhagic fever in west Africa.

  2014cited by this paper
• Emergence of Zaire Ebola virus disease in Guinea.

  2014cited by this paper
• Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak

  2014cited by this paper
• Establishment and Characterization of a Lethal Mouse Model for the Angola Strain of Marburg Virus

  2014cited by this paper
• Analysis of the Highly Diverse Gene Borders in Ebola Virus Reveals a Distinct Mechanism of Transcriptional Regulation

  2014cited by this paper
• Ebola virus disease in West Africa--the first 9 months of the epidemic and forward projections.

  2014cited by this paper
• An Upstream Open Reading Frame Modulates Ebola Virus Polymerase Translation and Virus Replication

  2013cited by this paper
• Ebola Virus RNA Editing Depends on the Primary Editing Site Sequence and an Upstream Secondary Structure

  2013cited by this paper
• Mutational and fitness landscapes of an RNA virus revealed through population sequencing

  2013cited by this paper
• The spatio-temporal distribution dynamics of Ebola virus proteins and RNA in infected cells

  2013cited by this paper
• Ebola Virus Genome Plasticity as a Marker of Its Passaging History: A Comparison of In Vitro Passaging to Non-Human Primate Infection

  2012cited by this paper
• Molecular Evolution of Viruses of the Family Filoviridae Based on 97 Whole-Genome Sequences

  2012cited by this paper
• Guide for the Care and Use of Laboratory Animals (8th edn)

  2012cited by this paper
• Inclusion Bodies Are a Site of Ebolavirus Replication

  2012cited by this paper
• Genomic RNA editing and its impact on Ebola virus adaptation during serial passages in cell culture and infection of guinea pigs.

  2011cited by this paper
• A New Ebola Virus Nonstructural Glycoprotein Expressed through RNA Editing

  2011cited by this paper
• Protein kinase PKR and RNA adenosine deaminase ADAR1: new roles for old players as modulators of the interferon response.

  2011influential reference
• Key Genomic Changes Necessary for an In Vivo Lethal Mouse Marburgvirus Variant Selection Process

  2011cited by this paper
• Ebola haemorrhagic fever.

  2011cited by this paper
• RNA editing enzyme adenosine deaminase is a restriction factor for controlling measles virus replication that also is required for embryogenesis

  2010cited by this paper
• Ebola and marburg hemorrhagic fever.

  2010cited by this paper
• RNA-specific Adenosine Deaminase ADAR1 Suppresses Measles Virus-induced Apoptosis and Activation of Protein Kinase PKR*

  2009cited by this paper
• Characterization of Ebolavirus regulatory genomic regions.

  2009cited by this paper
• Paramyxovirus mRNA editing, the "rule of six" and error catastrophe: a hypothesis.

  2005cited by this paper
• Viral RNA-polymerases -- a predicted 2'-O-ribose methyltransferase domain shared by all Mononegavirales.

  2002cited by this paper
• Ebola Virus VP30-Mediated Transcription Is Regulated by RNA Secondary Structure Formation

  2002cited by this paper
• Recovery of Infectious Ebola Virus from Complementary DNA: RNA Editing of the GP Gene and Viral Cytotoxicity

  2001cited by this paper
• Molecular characterization of guinea pig-adapted variants of Ebola virus.

  2000cited by this paper
• The importance of internal loops within RNA substrates of ADAR1.

  1999cited by this paper
• Transcriptional fidelity and proofreading by RNA polymerase II.

  1998cited by this paper
• The virion glycoproteins of Ebola viruses are encoded in two reading frames and are expressed through transcriptional editing.

  1996cited by this paper
• GP mRNA of Ebola virus is edited by the Ebola virus polymerase and by T7 and vaccinia virus polymerases.

  1995cited by this paper
• Preferential selection of adenosines for modification by double‐stranded RNA adenosine deaminase.

  1994cited by this paper
• Sequence analysis of the Ebola virus genome: organization, genetic elements, and comparison with the genome of Marburg virus.

  1993cited by this paper
• Marburg virus, a filovirus: messenger RNAs, gene order, and regulatory elements of the replication cycle.

  1992cited by this paper
• Numerous transitions in human parainfluenza virus 3 RNA recovered from persistently infected cells.

  1991cited by this paper
• Biased hypermutation and other genetic changes in defective measles viruses in human brain infections

  1988cited by this paper
• Homozygous deletion of the alpha- and beta 1-interferon genes in human leukemia and derived cell lines.

  1988cited by this paper
• Identification and analysis of Ebola virus messenger RNA.

  1987cited by this paper
• Transcriptional and posttranscriptional regulation of exogenous human beta interferon gene in simian cells defective in interferon synthesis

  1986cited by this paper
• Vesicular stomatitis virus defective interfering particles can contain extensive genomic sequence rearrangements and base substitutions.

  1984cited by this paper
• Localized attenuation and discontinuous synthesis during vesicular stomatitis virus transcription.

  1981cited by this paper

• Evidence that hPIV2 paramyxovirus antigenomes are edited during infection

  2025cites this paper
• Phylogenetic analysis of the promoter element 2 of paramyxo- and filoviruses

  2024cites this paper
• How does the polymerase of non-segmented negative strand RNA viruses commit to transcription or genome replication?

  2024cites this paper
• Secondary structure propensities of the Ebola delta peptide E40 in solution and model membrane environments.

  2024cites this paper
• N6-methyladenosine is required for efficient RNA synthesis of Ebola virus and other haemorrhagic fever viruses

  2023cites this paper
• Emergence of biased hypermutation in a heterologous additional transcription unit in recombinant lentogenic Newcastle disease virus.

  2023cites this paper
• Linked Mutations in the Ebola Virus Polymerase Are Associated with Organ Specific Phenotypes

  2023cites this paper
• Emergence of Marburg virus: a global perspective on fatal outbreaks and clinical challenges

  2023cites this paper
• Ebola virus delta peptide is an enterotoxin.

  2022cites this paper
• Influence of viral genome properties on polymerase fidelity.

  2022cites this paper
• Recombinant Lloviu virus as a tool to study viral replication and host responses

  2022cites this paper
• Differential regulation of interferon responses by Ebola and Differential regulation of interferon responses by Ebola and Marburg virus VP35 proteins Marburg virus VP35 proteins

  2022cites this paper
• Ubiquitination of Ebola virus VP35 at lysine 309 regulates viral transcription and assembly

  2022cites this paper
• Enterotoxigenic Escherichia coli Heat-Stable Toxin and Ebola Virus Delta Peptide: Similarities and Differences

  2022cites this paper
• Marburg and Ebola Virus mRNA 3′ Untranslated Regions Contain Negative Regulators of Translation That Are Modulated by ADAR1 Editing

  2021influential citation
• Unconventional viral gene expression mechanisms as therapeutic targets

  2021cites this paper
• New Perspectives on the Biogenesis of Viral Inclusion Bodies in Negative-Sense RNA Virus Infections

  2021cites this paper
• Recombinant Lloviu virus as a model to study inaccessible zoonotic viruses

  2021cites this paper
• ADAR Editing in Viruses: An Evolutionary Force to Reckon with

  2021cites this paper
• Identification and characterization of short leader and trailer RNAs synthesized by the Ebola virus RNA polymerase

  2021cites this paper
• Phylodynamic study of the conserved RNA structure encompassing the hemagglutinin cleavage site encoding region of H5 and H7 low pathogenic avian influenza viruses

  2021cites this paper
• Sendai Virus and a Unified Model of Mononegavirus RNA Synthesis

  2021cites this paper
• Variation around the dominant viral genome sequence contributes to viral load and outcome in patients with Ebola virus disease

  2020cites this paper
• A paramyxovirus-like model for Ebola virus bipartite promoters

  2020cites this paper
• Evolutionary history of cotranscriptional editing in the paramyxoviral phosphoprotein gene

  2020cites this paper
• Species-Specific Evolution of Ebola Virus during Replication in Human and Bat Cells

  2020cites this paper
• RNA secondary structure at the transcription start site influences EBOV transcription initiation and replication in a length- and stability-dependent manner

  2020cites this paper
• Regulation of VP30-Dependent Transcription by RNA Sequence and Structure in the Genomic Ebola Virus Promoter

  2020cites this paper
• Immunoinformatics Approach Identified Two Highly Conserved B and T Cell Epitopes, LEASKRWAF and DSPLEASKRWAFRTG, for Effective Vaccine Design against Ebola and Marburg Viruses

  2019cites this paper
• Epidemiological Trends and Current Challenges in Ebola: Pathogen Biology, Drug Targets, and Therapeutic Strategies

  2019cites this paper
• Transcriptomic profiles of striped snakehead cells (SSN‐1) infected with snakehead vesiculovirus (SHVV) identifying IFI35 as a positive factor for SHVV replication

  2019cites this paper
• Determinants of patient survival following acute Ebola virus infection

  2019cites this paper
• Recent advances in marburgvirus research

  2019cites this paper
• T-705 induces lethal mutagenesis in Ebola and Marburg populations in macaques.

  2019cites this paper
• Distinct genome replication and transcription strategies within the growing filovirus family.

  2019cites this paper
• Sudan Ebolavirus VP35-NP Crystal Structure Reveals a Potential Target for Pan-Filovirus Treatment

  2019influential citation
• Bipartite promoters and RNA editing of paramyxoviruses and filoviruses

  2018cites this paper
• Coupling Large-Scale Omics Data for Deciphering Systems Complexity

  2018cites this paper
• Title Transcriptional slippage in the positive-sense RNA virus family

  2018cites this paper
• A survey on cellular RNA editing activity in response to Candida albicans infections

  2018cites this paper
• Active Ebola Virus Replication and Heterogeneous Evolutionary Rates in EVD Survivors

  2018cites this paper
• Mechanisms and Concepts in RNA Virus Population Dynamics and Evolution.

  2018cites this paper
• Transcriptional analysis of viral mRNAs reveals common transcription patterns in cells infected by five different filoviruses

  2018cites this paper
• The methyltransferase domain of the Sudan ebolavirus L protein specifically targets internal adenosines of RNA substrates, in addition to the cap structure

  2018cites this paper
• Host Factors Involved in Ebola Virus Replication.

  2018cites this paper
• Evaluation of a rapid and sensitive RT-qPCR assay for the detection of Ebola Virus.

  2018cites this paper
• Ebola virus, but not Marburg virus, replicates efficiently and without required adaptation in snake cells

  2018cites this paper
• Comparative Transcriptomics Highlights the Role of the Activator Protein 1 Transcription Factor in the Host Response to Ebolavirus

  2017cites this paper
• Human transmission of Ebola virus.

  2017cites this paper
• Ebola virus VP24 interacts with NP to facilitate nucleocapsid assembly and genome packaging

  2017cites this paper
• Inside the Cell: Assembly of Filoviruses.

  2017cites this paper
• Stimulation of reverse transcriptase generated cDNAs with specific indels by template RNA structure: retrotransposon, dNTP balance, RT-reagent usage

  2017cites this paper
• Ebola Virus Disease: Biology, Diagnosis, Treatment and Prevention of Epidemics

  2017cites this paper
• Specific reverse transcriptase slippage at the HIV ribosomal frameshift sequence: potential implications for modulation of GagPol synthesis

  2017cites this paper
• Identification and functional characterization of P1N-PISPO, a new gene product present in sweet potato potyviruses

  2016cites this paper
• Ribosomal frameshifting and transcriptional slippage: From genetic steganography and cryptography to adventitious use

  2016cites this paper
• Differential Regulation of Interferon Responses by Ebola and Marburg Virus VP35 Proteins.

  2016cites this paper
• Ebola Virus Does Not Induce Stress Granule Formation during Infection and Sequesters Stress Granule Proteins within Viral Inclusions

  2016cites this paper
• A Universal Next-Generation Sequencing Protocol To Generate Noninfectious Barcoded cDNA Libraries from High-Containment RNA Viruses

  2016cites this paper
• Novel Chemical Ligands to Ebola Virus and Marburg Virus Nucleoproteins Identified by Combining Affinity Mass Spectrometry and Metabolomics Approaches

  2016cites this paper
• The P1N-PISPO trans-Frame Gene of Sweet Potato Feathery Mottle Potyvirus Is Produced during Virus Infection and Functions as an RNA Silencing Suppressor

  2016cites this paper
• A hamster model for Marburg virus infection accurately recapitulates Marburg hemorrhagic fever

  2016cites this paper
• Genomic characterization of serial-passaged Ebola virus in a boa constrictor cell line

  2016cites this paper
• Transcriptional Regulation in Ebola Virus: Effects of Gene Border Structure and Regulatory Elements on Gene Expression and Polymerase Scanning Behavior

  2015cites this paper
• Characterization of Immune Responses Induced by Ebola Virus Glycoprotein (GP) and Truncated GP Isoform DNA Vaccines and Protection Against Lethal Ebola Virus Challenge in Mice.

  2015cites this paper
• Charakterisierung der RNA-Bindungsaktivität von VP30 im Hinblick auf die virale Transkriptionsregulation des Ebolavirus

  2015influential citation
• An Intrinsically Disordered Peptide from Ebola Virus VP35 Controls Viral RNA Synthesis by Modulating Nucleoprotein-RNA Interactions.

  2015cites this paper
• Soluble Glycoprotein Is Not Required for Ebola Virus Virulence in Guinea Pigs.

  2015cites this paper
• RNA Polymerase Slippage as a Mechanism for the Production of Frameshift Gene Products in Plant Viruses of the Potyviridae Family

  2015cites this paper
• High-Throughput Minigenome System for Identifying Small-Molecule Inhibitors of Ebola Virus Replication.

  2015cites this paper
• Ebolavirus comparative genomics

  2015cites this paper
• Transcriptional slippage in the positive-sense RNA virus family Potyviridae

  2015cites this paper
• Three minimal sequences found in Ebola virus genomes and absent from human DNA

  2015cites this paper
• Local Mutational Pressures in Genomes of Zaire Ebolavirus and Marburg Virus

  2015influential citation
• Modeling of the Ebola Virus Delta Peptide Reveals a Potential Lytic Sequence Motif

  2015cites this paper
• Genotypic anomaly in Ebola virus strains circulating in Magazine Wharf area, Freetown, Sierra Leone, 2015.

  2015cites this paper
• Genetic Changes at the Glycoprotein Editing Site Associated With Serial Passage of Sudan Virus.

  2015cites this paper
• Filovirus pathogenesis and immune evasion: insights from Ebola virus and Marburg virus

  2015cites this paper
• Advances and Applications in Bioinformatics and Chemistry Dovepress in Silico-based Vaccine Design against Ebola Virus Glycoprotein

  year unknowncites this paper