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Epitranscriptomic Enhancement of Influenza A Virus Gene Expression and Replication.

ABSTRACT: Many viral RNAs are modified by methylation of the N6 position of adenosine (m6A). m6A is thought to regulate RNA splicing, stability, translation, and secondary structure. Influenza A virus (IAV) expresses m6A-modified RNAs, but the effects of m6A on this segmented RNA virus remain unclear. We demonstrate that global inhibition of m6A addition inhibits IAV gene expression and replication. In contrast, overexpression of the cellular m6A "reader" protein YTHDF2 increases IAV gene expression and replication. To address whether m6A residues modulate IAV RNA function in cis, we mapped m6A residues on the IAV plus (mRNA) and minus (vRNA) strands and used synonymous mutations to ablate m6A on both strands of the hemagglutinin (HA) segment. These mutations inhibited HA mRNA and protein expression while leaving other IAV mRNAs and proteins unaffected, and they also resulted in reduced IAV pathogenicity in mice. Thus, m6A residues in IAV transcripts enhance viral gene expression.

SUBMITTER: Courtney DG

PROVIDER: S-EPMC5615858 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Epitranscriptomic Enhancement of Influenza A Virus Gene Expression and Replication.

Courtney David G DG Kennedy Edward M EM Dumm Rebekah E RE Bogerd Hal P HP Tsai Kevin K Heaton Nicholas S NS Cullen Bryan R BR

Cell host & microbe 20170901 3

Many viral RNAs are modified by methylation of the N6 position of adenosine (m6A). m6A is thought to regulate RNA splicing, stability, translation, and secondary structure. Influenza A virus (IAV) expresses m6A-modified RNAs, but the effects of m6A on this segmented RNA virus remain unclear. We demonstrate that global inhibition of m6A addition inhibits IAV gene expression and replication. In contrast, overexpression of the cellul ...[more]

PMID: 28910636

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Project description:Heldt2012 - Influenza Virus Replication The model describes the life cycle of influenza A virus in a mammalian cell including the following steps: attachment of parental virions to the cell membrane, receptor-mediated endocytosis, fusion of the virus envelope with the endosomal membrane, nuclear import of vRNPs, viral transcription and replication, translation of the structural viral proteins, nuclear export of progeny vRNPs and budding of new virions. It also explicitly accounts for the stabilization of cRNA by viral polymerases and NP and the inhibition of vRNP activity by M1 protein binding. In short, the model focuses on the molecular mechanism that controls viral transcription and replication. This model is described in the article: Modeling the intracellular dynamics of influenza virus replication to understand the control of viral RNA synthesis. Heldt FS, Frensing T, Reichl U. J Virol. Abstract: Influenza viruses transcribe and replicate their negative-sense RNA genome inside the nucleus of host cells via three viral RNA species. In the course of an infection, these RNAs show distinct dynamics, suggesting that differential regulation takes place. To investigate this regulation in a systematic way, we developed a mathematical model of influenza virus infection at the level of a single mammalian cell. It accounts for key steps of the viral life cycle, from virus entry to progeny virion release, while focusing in particular on the molecular mechanisms that control viral transcription and replication. We therefore explicitly consider the nuclear export of viral genome copies (vRNPs) and a recent hypothesis proposing that replicative intermediates (cRNA) are stabilized by the viral polymerase complex and the nucleoprotein (NP). Together, both mechanisms allow the model to capture a variety of published data sets at an unprecedented level of detail. Our findings provide theoretical support for an early regulation of replication by cRNA stabilization. However, they also suggest that the matrix protein 1 (M1) controls viral RNA levels in the late phase of infection as part of its role during the nuclear export of viral genome copies. Moreover, simulations show an accumulation of viral proteins and RNA toward the end of infection, indicating that transport processes or budding limits virion release. Thus, our mathematical model provides an ideal platform for a systematic and quantitative evaluation of influenza virus replication and its complex regulation. With the current parameter set, the model reproduces an infection at a multiplicity of infection (MOI) of 10. Figure 2A of the paper is reproduced here, with parameters kDegRnp and kSynP changed to zeros. Initial conditions and parameter changes that were used to obtain specific figures in the article can be found in Table A2. The model has the correct value for kAttLo as 4.55e-04. The value of this parameter mentioned as 4.55e-02 in Table 1 of the paper is incorrect. This is checked with the author. This model is hosted on BioModels Database and identified by: MODEL1307270000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

Epitranscriptomic Enhancement of Influenza A Virus Gene Expression and Replication.

Publications

Epitranscriptomic Enhancement of Influenza A Virus Gene Expression and Replication.

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