Transcriptional analysis of ZX-7101 treatment.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE225905 | GEO | 2023/08/23
REPOSITORIES: GEO
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Project description:Airway epithelial cells are the initial site of infection with influenza viruses. The innate immune responses of airway epithelial cells to infection have the potential to limit virus replication and induce effective adaptive immune responses. However, relatively little is known about the importance of this innate anti-viral response to infection. Avian influenza viruses are a potential source of future pandemics, therefore it is critical to examine the effectiveness of the host anti-viral system to different influenza viruses. We used a human influenza (H3N2) and a low pathogenic avian influenza (H11N9) to assess and compare the anti-viral responses of bronchial epithelial cells (BECs). After infection, the H3N2 virus replicated more effectively than the H11N9 strain in BECs. This was not due to differential expression of different sialic acid residues on BECs but was attributed to the interference of the host anti-viral responses by H3N2. The H3N2 strain induced a delay in anti-viral signaling and impaired release of type I and type III interferons (IFNs) compared to the H11N9 virus. We then transfected the gene encoding for non-structural (NS) 1 protein into the BECs and the H3N2 NS1 induced a greater inhibition of anti-viral responses compared to the H11N9 NS1. While the low pathogenic avian influenza virus was capable of infecting BECs, the human influenza virus replicated more effectively than avian influenza virus in BECs and this may be at least in part due to a differential ability of the two NS1 proteins to inhibit anti-viral responses. This suggests that the subversion of human anti-viral responses may be an important requirement for influenza viruses to adapt to the human host and induce disease.
2009-12-19 | GSE19580 | GEO
Project description:Influenza A virus (IAV) infection causes acute respiratory disease with potential severe and deadly complications. Viral pathogenesis is not only due to the direct cytopathic effect of viral infections but also to the exacerbated host inflammatory responses. Influenza viral infection can activate various host signaling pathways that function to activate or inhibit viral replication. Our previous studies have shown that a receptor tyrosine kinase TrkA plays an important role in the replication of influenza viruses in vitro, but its biological roles and functional mechanisms in influenza viral infection have not been characterized. Here we show that IAV infection strongly activates TrkA in vitro and in vivo. Using a chemical-genetic approach to specifically control TrkA kinase activity through a small molecule compound 1NMPP1 in a TrkA knock-in (TrkA KI) mouse model, we show that 1NMPP1-mediated TrkA inhibition completely protected mice from a lethal IAV infection by significantly reducing viral loads and lung inflammation. Using primary lung cells isolated from the TrkA KI mice, we show that specific TrkA inhibition reduced viral RNA synthesis in airway epithelial cells (AECs) but not in alveolar macrophages (AMs). Transcriptomic analysis confirmed the cell-type-specific role of TrkA in viral RNA synthesis, and identified distinct gene expression patterns under the TrkA regulation in IAV-infected AECs and AMs. Among the TrkA-activated targets are various proinflammatory cytokines and chemokines such as IL6, IL-1, IFNs, CCL-5, and CXCL9, supporting the role of TrkA in mediating lung inflammation. Indeed, TrkA inhibitor 1NMPP1 administered after the peak of IAV replication, though had no effect on viral load, was able to decrease lung inflammation and provide partial protection in mice. Taken together, our results have demonstrated for the first time an important biological role of TrkA signaling in IAV infection, identified its cell-type-specific contribution to viral replication, and revealed its functional mechanism in virus-induced lung inflammation. This study suggests TrkA as a novel host target for therapeutics against influenza viral disease.
2022-09-05 | GSE203539 | 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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2024-09-02 | BIOMD0000000463 | BioModels
Project description:The highly pathogenic avian influenza (HPAI) H5N1 viruses continue to circulate in nature and threaten public health. Although several viral determinants and host factors that influence the virulence of HPAI H5N1 viruses in mammals have been identified, the detailed molecular mechanism remains poorly defined and requires further clarification. In our previous studies, we characterized two naturally isolated HPAI H5N1 viruses that had similar viral genomes but differed substantially in their lethality in mice. Here, we explored the molecular determinants and potential mechanism for this difference in virulence. By using reverse genetics, we found that a single amino acid at position 158 of the hemagglutinin (HA) protein substantially affected the systemic replication and pathogenicity of these H5N1 influenza viruses in mice. We further found that the G158N mutation introduced an N-linked glycosylation at sites 158–160 of the HA protein and that this N-linked glycosylation enhanced viral productivity in infected mammalian cells and induced stronger host immune and inflammatory responses to viral infection. These findings further our understanding of the determinants of pathogenicity of H5N1 viruses in mammals.
2016-12-22 | GSE89246 | GEO
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.
2015-11-05 | GSE58741 | GEO
Project description:In addition to directly inhibiting viral proteins, some antiviral drugs inhibit virus replication through regulation of host gene expression. Here we test whether antiviral activity of antivirals is independent of modulating gene expression in infected host cells.
2023-07-17 | GSE232189 | GEO
Project description:In addition to directly inhibiting viral proteins, some antiviral drugs inhibit virus replication through regulation of host gene expression. Here we test whether antiviral activity of antivirals is independent of modulating gene expression in infected host cells.
2022-12-01 | GSE194130 | GEO
Project description:RIG-I is thought to be the most important sensor of influenza virus infection and plays critical roles in the recognition of cytoplasmic dsRNA and activation of type I IFNs and initiates the innate antiviral immune responses. How the binding of viral RNA to and activation of RIG-I are regulated remains enigmatic. Here, by an affinity proteomics approach with viral RNA as the bait, we found that IFI16, previously identified as a DNA sensor, was significantly induced both in vitro and in vivo during influenza virus infection. Using an IFI16 knockout cells and p204-deficient mice model, we demonstrated that IFI16 enhanced RIG-I-mediated production of type I IFNs and thereby inhibited viral replication during influenza virus infection. Furthermore, we showed that IFI16 regulated the RIG-I signaling by enhancing its transcriptional expression through recruitment of RNA Pol II to the RIG-I promoter. We also verified that IFI16 directly interacted with both viral RNA by HINa domain and associated with RIG-I through its PYRIN domain as well as promoted influenza virus-induced K63-linked polyubiquitination of RIG-I. In addition, we found that IFI16 lost its ability to inhibit viral replication in the absence of RIG-I in virus-infected cells. These results indicate that IFI16 is a key regulator of the RIG-I signaling during antiviral innate immune responses, which highlights a novel mechanism of IFI16 in IAV and other RNA viruses infection, expands our knowledge in antiviral innate immunity, and suggests its possible use as a new strategies to manipulate antiviral responses.
2020-09-09 | GSE157609 | GEO
Project description:RIG-I is thought to be the most important sensor of influenza virus infection and plays critical roles in the recognition of cytoplasmic dsRNA and activation of type I IFNs and initiates the innate antiviral immune responses. How the binding of viral RNA to and activation of RIG-I are regulated remains enigmatic. Here, by an affinity proteomics approach with viral RNA as the bait, we found that IFI16, previously identified as a DNA sensor, was significantly induced both in vitro and in vivo during influenza virus infection. Using an IFI16 knockout cells and p204-deficient mice model, we demonstrated that IFI16 enhanced RIG-I-mediated production of type I IFNs and thereby inhibited viral replication during influenza virus infection. Furthermore, we showed that IFI16 regulated the RIG-I signaling by enhancing its transcriptional expression through recruitment of RNA Pol II to the RIG-I promoter. We also verified that IFI16 directly interacted with both viral RNA by HINa domain and associated with RIG-I through its PYRIN domain as well as promoted influenza virus-induced K63-linked polyubiquitination of RIG-I. In addition, we found that IFI16 lost its ability to inhibit viral replication in the absence of RIG-I in virus-infected cells. These results indicate that IFI16 is a key regulator of the RIG-I signaling during antiviral innate immune responses, which highlights a novel mechanism of IFI16 in IAV and other RNA viruses infection, expands our knowledge in antiviral innate immunity, and suggests its possible use as a new strategies to manipulate antiviral responses.
2020-09-17 | GSE158122 | GEO
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).
2015-11-05 | E-GEOD-58741 | biostudies-arrayexpress