Similar Datasets
Project description:Human respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections in young children, the elderly, and immunocompromised individuals. Prior exposure to RSV affords little protection and many are susceptible to reinfection throughout life. Virally encoded non-structural (NS) protein 1 (NS1) is thought to modulate host responses in the cytosol. Here, we describe the nuclear localization of NS1 during RSV infection and a corresponding nuclear role in modulating host transcription. In support, we show that a significant proportion of NS1 is partitions to the nucleus and that NS1 alone is necessary and sufficient to translocate into the nucleus. NS1 co-localizes with exportin XPO1 and inhibition of XPO1 results in NS1 accumulation in the nucleus. Furthermore, nuclear NS1 is chromatin-associated and co-immunoprecipitates with Mediator complex proteins. Chromatin-immunoprecipitation demonstrates enrichment of NS1 binding overlapping Mediator and interferon-stimulated transcription factor binding sites that lie within regulatory elements of genes differentially expressed during RSV infection. Mutation of the unique alpha helix in NS1 enhances its repressive effect on host gene expression. Together, these data suggest that nuclear NS1 may alter host responses to RSV infection by binding at the promoters and enhancers of host immune response genes and disrupting host transcriptional regulators. Our study identifies yet another regulatory layer of interactions with RSV proteins that shapes host response to RSV and potentially impacts long-term immunity to RSV.
2021-10-12 | GSE155151 | GEO
Project description:Human respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections in young children, the elderly, and immunocompromised individuals. Prior exposure to RSV affords little protection and many are susceptible to reinfection throughout life. Virally encoded non-structural (NS) protein 1 (NS1) is thought to modulate host responses in the cytosol. Here, we describe the nuclear localization of NS1 during RSV infection and a corresponding nuclear role in modulating host transcription. In support, we show that a significant proportion of NS1 is partitions to the nucleus and that NS1 alone is necessary and sufficient to translocate into the nucleus. NS1 co-localizes with exportin XPO1 and inhibition of XPO1 results in NS1 accumulation in the nucleus. Furthermore, nuclear NS1 is chromatin-associated and co-immunoprecipitates with Mediator complex proteins. Chromatin-immunoprecipitation demonstrates enrichment of NS1 binding overlapping Mediator and interferon-stimulated transcription factor binding sites that lie within regulatory elements of genes differentially expressed during RSV infection. Mutation of the unique alpha helix in NS1 enhances its repressive effect on host gene expression. Together, these data suggest that nuclear NS1 may alter host responses to RSV infection by binding at the promoters and enhancers of host immune response genes and disrupting host transcriptional regulators. Our study identifies yet another regulatory layer of interactions with RSV proteins that shapes host response to RSV and potentially impacts long-term immunity to RSV.
2021-10-12 | GSE155150 | GEO
Project description:Human Respiratory Syncytial Virus Non-Structural Protein NS1 enters the nucleus to disrupt gene transcription
| PRJNA648855 | ENA
Project description:Human Respiratory Syncytial Virus Non-Structural Protein NS1 enters the nucleus to disrupt gene transcription (RNA-seq)
| PRJNA648862 | ENA
Project description:Human Respiratory Syncytial Virus Non-Structural Protein NS1 enters the nucleus to disrupt gene transcription (ChIP-seq)
| PRJNA648861 | ENA
Project description:Human respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections in the pediatric, elderly, and immunocompromised individuals. RSV non-structural protein NS1 is a known cytosolic immune antagonist, but how NS1 modulates host responses remains poorly defined. Here, we observe NS1 partitioning into the nucleus of RSV-infected cells, including the human airway epithelium. Nuclear NS1 coimmunoprecipitates with Mediator complex and is chromatin associated. Chromatin-immunoprecipitation demonstrates enrichment of NS1 that overlaps Mediator and transcription factor binding within the promoters and enhancers of differentially expressed genes during RSV infection. Mutation of the NS1 C-terminal helix reduces NS1 impact on host gene expression. These data suggest that nuclear NS1 alters host responses to RSV infection by binding at regulatory elements of immune response genes and modulating host gene transcription. Our study identifies another layer of regulation by virally encoded proteins that shapes host response and impacts immunity to RSV.
| S-EPMC8609347 | biostudies-literature
Project description:Human respiratory syncytial virus (RSV) is a major health challenge in the young and elderly owing to the lack of a safe and effective vaccine and proven antiviral drugs. Understanding the mechanisms by which viral genes and proteins modulate the host response to infection is critical for identifying novel disease intervention strategies. In this study, the RSV non-structural protein NS1 was shown to suppress miR-24 expression during infection. Lack of NS1 was linked to increased expression of miR-24, whilst NS1 overexpression suppressed miR-24 expression. NS1 was found to induce Kruppel-like factor 6 (KLF6), a transcription factor that positively regulates the transforming growth factor (TGF)-b pathway to induce cell cycle arrest. Silencing of KLF6 led to increased miR-24 expression via downregulation of TGF-?. Treatment with exogenous TGF-? suppressed miR-24 expression and induced KLF6. Confocal microscopy showed co-localization of KLF6 and RSV NS1. These findings indicated that RSV NS1 interacts with KLF6 and modulates miR-24 expression and TGF-?, which facilitates RSV replication.
| S-EPMC4806578 | biostudies-literature
Project description:Human respiratory syncytial virus (hRSV) is a major cause of morbidity and mortality in the pediatric, elderly, and immune compromised populations. A gap in our understanding of hRSVdisease pathology is the interplay between virally encoded immune antagonists and host components that limit hRSV replication. hRSV encodes for non-structural (NS) proteins that are important immune antagonists; however, the role of these proteins in viral pathogenesis is incompletely understood. Here we report the crystal structure of hRSV NS1 protein, which suggests that NS1 is a structural paralog of hRSV matrix (M) protein. Comparative analysis of the shared structural fold with M revealed regions unique to NS1. Studies on NS1 WT or mutant alone or in recombinant RSVs demonstrate that structural regions unique to NS1 contribute to modulation of host responses, including inhibition of type I IFN responses, suppression of dendritic cell maturation, and promotion of inflammatory responses. Transcriptional profiles of A549 cells infected with recombinant RSVs show significant differences in multiple host pathways, suggesting that NS1 may have a greater role in regulating host responses than previously appreciated. These results provide a framework to target NS1 for therapeutic development to limit hRSV associated morbidity and mortality.
2017-06-15 | GSE99298 | GEO
Project description:BackgroundHuman respiratory syncytial virus (RSV) is an important cause of lower respiratory tract disease in the paediatic population, immunocompromised individuals and the elderly worldwide. However, despite global efforts over the past several decades there are no commercially available vaccines. RSV encodes 2 non-structural proteins, NS1 and NS2, that are type I interferon antagonists. RSV restricts type I interferon signaling and the expression of antiviral genes by degrading STAT2. It has been proposed that NS1 binds to elongin C to form a ubiquitin ligase (E3) complex that targets STAT2 for ubiquitination and proteosomal degradation.ResultsHere, we have engineered a live recombinant RSV in which the 3 consensus amino acids of the NS1 elongin C binding domain have been replaced with alanine (NS1F-ELCmut). Mutation of this region of NS1 resulted in attenuation of RSV replication in A549 cells to levels similar to that observed when the NS1 gene is completely deleted (?NS1). This mutation also resulted in moderate attenuation in Vero cells. Attenuation was correlated to intracellular degradation of the mutated NS1 protein. Time course analysis showed that mutant NS1 protein accumulated in cytoplasmic bodies that contained the lysosomal marker LAMP1. However lack of cleavage of LC3 suggested that autophagy was not involved. Induction of IFN-? mRNA expression also was observed in association with the degradation of NS1 protein and attenuation of viral growth.ConclusionsThese results indicate that the elongin C binding region of NS1 is crucial for survival of the protein and that disruption of this region results in the degradation of NS1 and restriction of RSV replication.
| S-EPMC3121706 | biostudies-literature
Project description:Human respiratory syncytial virus (hRSV) is a major cause of morbidity and mortality in the paediatric, elderly and immune-compromised populations1,2. A gap in our understanding of hRSV disease pathology is the interplay between virally encoded immune antagonists and host components that limit hRSV replication. hRSV encodes for non-structural (NS) proteins that are important immune antagonists3-6; however, the role of these proteins in viral pathogenesis is incompletely understood. Here, we report the crystal structure of hRSV NS1 protein, which suggests that NS1 is a structural paralogue of hRSV matrix (M) protein. Comparative analysis of the shared structural fold with M revealed regions unique to NS1. Studies on NS1 wild type or mutant alone or in recombinant RSVs demonstrate that structural regions unique to NS1 contribute to modulation of host responses, including inhibition of type I interferon responses, suppression of dendritic cell maturation and promotion of inflammatory responses. Transcriptional profiles of A549 cells infected with recombinant RSVs show significant differences in multiple host pathways, suggesting that NS1 may have a greater role in regulating host responses than previously appreciated. These results provide a framework to target NS1 for therapeutic development to limit hRSV-associated morbidity and mortality.
| S-EPMC5739881 | biostudies-literature