Influenza virus replication intensity and round of infection dictates the cellular response in vivo
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ABSTRACT:
PROVIDER: PRJNA448991 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6954100.fastq.gz | Fastqsanger.gz | |||
| SRR6954110.fastq.gz | Fastqsanger.gz | |||
| SRR6954120.fastq.gz | Fastqsanger.gz | |||
| SRR6954130.fastq.gz | Fastqsanger.gz | |||
| SRR6954101.fastq.gz | Fastqsanger.gz |
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Project description:Influenza A virus has a broad cellular tropism in the respiratory tract. Infected epithelial cells sense the infection and initiate an antiviral response. To define the antiviral response at the earliest stages of infection we used two different single cycle replication reporter viruses. These tools demonstrated heterogeneity in virus replication levels in vivo. Transcriptional profiling demonstrated tiers of interferon stimulated gene responses that were dependent on the magnitude of virus replication. Uninfected cells and cells with blunted replication expressed a distinct and potentially protective ISG signature. Finally, we used these single cycle reporter viruses to determine the antiviral landscape during virus spread, which unveiled disparate protection mediated by IFN. Together these results highlight the complexity of virus-host interactions within the infected lung and suggest that magnitude and round of replication tune the antiviral response.
2018-09-20 | GSE112794 | GEO
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.
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Project description:Influenza A virus encodes promoters in both the sense and antisense orientations. These support the generation of new genomes, antigenomes, and mRNA transcripts. Characterization of the influenza promoters using minimal replication assays—transfections with viral polymerase, nucleoprotein, and a genomic template—defined their sequence as 13nt at the 5’ end of the viral genomic RNA (U13) and 12nt at the 3’ end (U12).Other than a single position the U12 and U13 sequences are identical between all eight RNA molecules that comprise the segmented influenza genome.Nevertheless, each segment can exhibit different transcriptional dynamics despite possessing identical promoters.Minimal replication assays lack the influenza protein NS2, which can modulate transcription and replication differentially between influenza segments.This suggests that NS2 expression may redefine the influenza A virus promoter.In this work we assess how internal regions of sequence in two genomic segments, HA and PB1, may contribute to NS2-dependent replication as well as map such interactions down to individual nucleotides in PB1. We find that the expression of NS2 significantly alters sequence requirements for efficient replication beyond the identical U12 and U13 sequence, providing a mechanism for the divergent replication and transcription dynamics across the influenza A virus genome.
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Project description:Influenza viruses pose a significant burden on global human health. Influenza has a broad cellular tropism in the airway, but how infection of different epithelial cell types impacts replication kinetics and burden in the airways is not fully understood. Using primary human airway cultures, which recapitulate the diverse epithelial cell landscape of the human airways, we investigated the impact of cell type composition on virus tropism and replication kinetics. Cultures were highly diverse across multiple donors and 30 independent differentiation conditions and supported a range of influenza replication. Although many cell types were susceptible to influenza, ciliated and secretory cells were predominantly infected. Despite the strong tropism preference for secretory and ciliated cells, which consistently make up 75% or more of infected cells, only ciliated cells were associated with increased virus production. Surprisingly, infected secretory cells were associated with overall reduced virus output. These data highlight the heterogeneous outcomes of influenza virus infections in primary human airway cultures and the disparate impacts of infected cell identity on burst size, even among preferentially infected cell types.
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Project description:Influenza is a major cause of morbidity and mortality worldwide, and the emerging drug resistance poses an increasing challenge to the treatment of influenza virus infection. Therefore, the development of a novel antiviral drugs has become an urgent task to combat against the influenza viruses that are resistant to the current therapeutic treatment. Here, by screening a small molecule chemical compound library, we identified 3-anhydro-6-epi-ophiobolin A (named L435) as a potent anti-influenza agent. Mechanistically, L435 markedly reduced influenza virus replication in vitro and in vivo. Importantly, L435 treatment improved the survival of influenza-virus-infected mice, suggesting that L435 may be a novel therapeutic agent for treatment of influenza virus infections. This microarray experiment was carried out to explore gene expression changes in influenza-virus-infected A549 cells after L435 treatment, and find out why L435 could inhibit the replication of influenza A virus. Total RNAs were extracted from three different groups of A549 cells that were mock treated, or infected with WSN and treated with DMSO for 12h, or infected with WSN and treated with L435 for 12 h, using TRIzol reagent (Invitrogen, Carlsbad, CA). Three independent experiments were performed. Samples were amplified and labeled using the One-Color Quick Amp Labeling Kit (Agilent p/n 5190-2305).
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Project description:Loss of the nuclear protein RTF2 enhances influenza replication
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