Evidence for a Crucial Role of a Host Non-coding RNA in Influenza A Virus Replication
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE45399 | GEO | 2014/01/29
SECONDARY ACCESSION(S): PRJNA194597
REPOSITORIES: GEO
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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2014-01-29 | E-GEOD-45399 | biostudies-arrayexpress
Project description:A growing body of evidence suggests the non-protein coding human genome is of vital importance for human cell function. Besides small RNAs, the diverse class of long non-coding RNAs (lncRNAs) recently came into focus. However, their relevance for infection, a major evolutionary driving force, remains elusive. Using two commercially available microarray systems, namely NCode™ and Sureprint™ G3, we identified differential expression of 42 ncRNAs during influenza A virus (IAV) infection in human lung epithelial cells. This included several classes of lncRNAs, including large intergenic ncRNAs (lincRNAs). As analyzed by qRT-PCR, expression of one lincRNA, which we termed virus inducible lincRNA (VIN), is induced by several IAV strains (H1N1, H3N2, H7N7) as well as vesicular stomatitis virus. However, we did not observe an induction of VIN by influenza B virus, treatment with RNA mimics, or IFN?. Thus, VIN expression seems to be a specific response to certain viral infections. RNA fractionation and RNA-FISH experiments revealed that VIN is localized to the host cell nucleus. Most importantly, we show that abolition of VIN by RNA interference restricts IAV replication and viral protein synthesis, highlighting the relevance of this lincRNA for productive IAV infection. Our observations suggest that viral pathogens interfere with the non-coding portion of the human genome, thereby guaranteeing their successful propagation, and that the expression of VIN correlates with their virulence. Consequently, our study provides a novel approach for understanding virus pathogenesis in greater detail, which will enable future design of new antiviral strategies targeting the host's non-protein coding genome.
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Project description:Influenza A virus is an RNA virus that encodes up to 11 proteins and this small coding capacity demands that the virus use the host cellular machinery for many aspects of its life cycle. Knowledge of these host cell requirements not only informs us of the molecular pathways exploited by the virus but also provides further targets that could be pursued for antiviral drug development. Here we use an integrative systems approach, based on genome-wide RNA interference screening, to identify 295 cellular cofactors required for early-stage influenza virus replication. Within this group, those involved in kinase-regulated signalling, ubiquitination and phosphatase activity are the most highly enriched, and 181 factors assemble into a highly significant host-pathogen interaction network. Moreover, 219 of the 295 factors were confirmed to be required for efficient wild-type influenza virus growth, and further analysis of a subset of genes showed 23 factors necessary for viral entry, including members of the vacuolar ATPase (vATPase) and COPI-protein families, fibroblast growth factor receptor (FGFR) proteins, and glycogen synthase kinase 3 (GSK3)-beta. Furthermore, 10 proteins were confirmed to be involved in post-entry steps of influenza virus replication. These include nuclear import components, proteases, and the calcium/calmodulin-dependent protein kinase (CaM kinase) IIbeta (CAMK2B). Notably, growth of swine-origin H1N1 influenza virus is also dependent on the identified host factors, and we show that small molecule inhibitors of several factors, including vATPase and CAMK2B, antagonize influenza virus replication.
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Project description:This SuperSeries is composed of the SubSeries listed below.
2012-04-10 | GSE36555 | GEO
Project description:Genetic drift of influenza virus genomic sequences occurs through the combined effects of sequence alterations introduced by a low-fidelity polymerase and the varying selective pressures experienced as the virus migrates through different host environments. While traditional phylogenetic analysis is useful in tracking the evolutionary heritage of these viruses, the specific genetic determinants that dictate important phenotypic characteristics are often difficult to discern within the complex genetic background arising through evolution. Here we describe a novel influenza virus sequence feature variant type (Flu-SFVT) approach, made available through the public Influenza Research Database resource (www.fludb.org), in which variant types (VTs) identified in defined influenza virus protein sequence features (SFs) are used for genotype-phenotype association studies. Since SFs have been defined for all influenza virus proteins based on known structural, functional, and immune epitope recognition properties, the Flu-SFVT approach allows the rapid identification of the molecular genetic determinants of important influenza virus characteristics and their connection to underlying biological functions. We demonstrate the use of the SFVT approach to obtain statistical evidence for effects of NS1 protein sequence variations in dictating influenza virus host range restriction.
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Project description:Influenza virus infection through seasonal epidemics and occasional pandemics has been a major public health concern for decades. Incomplete protection from vaccination and increased antiviral resistance due to frequent mutations of influenza viruses have led to a continuous need for new therapeutic options. The functional significance of host protein and influenza virus interactions has been established, but relatively less is known about the interaction of host noncoding RNAs, including microRNAs and long noncoding RNAs, with influenza viruses. In this review, we summarize host noncoding RNA profiles during influenza virus infection and the regulation of influenza virus infection by host noncoding RNAs. Influenza viral non-coding RNAs are briefly discussed. Increased understanding of the molecular regulation of influenza viral replication will be beneficial in identifying potential therapeutic targets against the influenza virus.
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Project description:Early events of the human immunodeficiency virus 1 (HIV-1) lifecycle, such as post-entry virus trafficking, uncoating and nuclear import, are poorly characterized because of limited understanding of virus-host interactions. Here, we used mass spectrometry-based proteomics to delineate cellular binding partners of curved HIV-1 capsid lattices and identified Sec24C as an HIV-1 host dependency factor. Gene deletion and complementation in Jurkat cells revealed that Sec24C facilitates infection and markedly enhances HIV-1 spreading infection. Downregulation of Sec24C in HeLa cells substantially reduced HIV-1 core stability and adversely affected reverse transcription, nuclear import and infectivity. Live-cell microscopy showed that Sec24C co-trafficked with HIV-1 cores in the cytoplasm during virus ingress. Biochemical assays demonstrated that Sec24C directly and specifically interacted with hexameric capsid lattices. A 2.3-Å resolution crystal structure of Sec24C228-242 in the complex with a capsid hexamer revealed that the Sec24C FG-motif bound to a pocket comprised of two adjoining capsid subunits. Combined with previous data1-4, our findings indicate that a capsid-binding FG-motif is conserved in unrelated proteins present in the cytoplasm (Sec24C), the nuclear pore (Nup153; refs. 3,4) and the nucleus (CPSF6; refs. 1,2). We propose that these virus-host interactions during HIV-1 trafficking across different cellular compartments are crucial for productive infection of target cells.
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Project description:Human protein kinases (HPKs) have profound effects on cellular responses. To better understand the role of HPKs and the signaling networks that influence influenza virus replication, a small interfering RNA (siRNA) screen of 720 HPKs was performed. From the screen, 17 HPKs (NPR2, MAP3K1, DYRK3, EPHA6, TPK1, PDK2, EXOSC10, NEK8, PLK4, SGK3, NEK3, PANK4, ITPKB, CDC2L5 (CDK13), CALM2, PKN3, and HK2) were validated as essential for A/WSN/33 influenza virus replication, and 6 HPKs (CDK13, HK2, NEK8, PANK4, PLK4 and SGK3) were identified as vital for both A/WSN/33 and A/New Caledonia/20/99 influenza virus replication. These HPKs were found to affect multiple host pathways and regulated by miRNAs induced during infection. Using a panel of miRNA agonists and antagonists, miR-149* was found to regulate NEK8 expression, miR-548d-3p was found to regulate MAPK1 transcript expression, and miRs -1228 and -138 to regulate CDK13 expression. Up-regulation of miR-34c induced PLK4 transcript and protein expression and enhanced influenza virus replication, while miR-34c inhibition reduced viral replication. These findings identify HPKs important for influenza viral replication and show the miRNAs that govern their expression.
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Project description:Pandemic influenza viruses modulate proinflammatory responses that can lead to immunopathogenesis. We present an extensive and systematic profiling of lipids, metabolites, and proteins in respiratory compartments of ferrets infected with either 1918 or 2009 human pandemic H1N1 influenza viruses. Integrative analysis of high-throughput omics data with virologic and histopathologic data uncovered relationships between host responses and phenotypic outcomes of viral infection. Proinflammatory lipid precursors in the trachea following 1918 infection correlated with severe tracheal lesions. Using an algorithm to infer cell quantity changes from gene expression data, we found enrichment of distinct T cell subpopulations in the trachea. There was also a predicted increase in inflammatory monocytes in the lung of 1918 virus-infected animals that was sustained throughout infection. This study presents a unique resource to the influenza research community and demonstrates the utility of an integrative systems approach for characterization of lipid metabolism alterations underlying respiratory responses to viruses.
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Project description:The incidence of cancer continues to grow and is one of the leading causes of death in the world. Long noncoding RNAs (LncRNAs) is a group of RNA transcripts greater than 200 nucleotides in length, and although it cannot encode proteins, it can regulate different biological functions by controlling gene expression, transcription factors, etc. LncRNA micro-chromosome maintenance protein 3-associated protein antisense RNA 1 (MCM3AP-AS1) is involved in RNA processing and cell cycle-related functions, and MCM3AP-AS1 is dysregulated in expression in various types of cancers. This biomarker is involved in many processes related to carcinogens, such as cell proliferation, apoptosis, cell cycle, and migration. In this review, we summarize the roles of MCM3AP-AS1 in different human cancers and its biological functions with a view to providing ideas for future research.
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