HUMAN-VIRUS CHIMERIC PROTEINS GENERATED DURING INFECTION
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE148245 | GEO | 2020/05/15
REPOSITORIES: GEO
Similar Datasets
Project description:Influenza A virus (IAV) lacks the enzyme for adding 5â caps to its RNAs, and thus snatches the 5â ends of host capped RNAs to prime transcription. Neither the preference of the host RNA sequences snatched, nor the effect of âcap-snatchingâ on host processes has been completely defined. Previous studies of influenza cap-snatching used poly(A)-selected RNA from infected cells or relied solely on annotated host protein-coding genes to define host mRNAs selected by the virus. To examine the substrate-product relationship between all host RNAs, including non-coding RNAs, and viral RNAs, we used an unbiased approach to identify the host and viral capped RNAs from IAV-infected cells. We demonstrate that IAV predominantly snatches caps from non-coding host RNAs, particularly U1 and U2 small nuclear RNAs (snRNAs). Because snRNAs regulate host mRNA processing, cap-snatching of snRNAs may constitute a means by which IAV hijacks host cell metabolism. examine caps snatched by influenza virus A
2015-11-23 | E-GEOD-67493 | biostudies-arrayexpress
Project description:We report a novel mechanism of gene origination in the segmented negative sense viruses (sNSVs), including IAV and LASV. During replication, these viruses use "snatched" host caps to prime their own transcription (cap-snatching). We show that a proportion of cap-snatched host sequences contain translational start codons (AUGs), that are recognized by the host ribosome. This allows for the translation of host and viral “untranslated regions” (UTRs) to create N-terminally extended viral proteins or entirely novel polypeptides by genetic overprinting.
2020-05-31 | GSE148122 | GEO
Project description:Influenza A virus (IAV) lacks the enzyme for adding 5’ caps to its RNAs, and thus snatches the 5’ ends of host capped RNAs to prime transcription. Neither the preference of the host RNA sequences snatched, nor the effect of “cap-snatching” on host processes has been completely defined. Previous studies of influenza cap-snatching used poly(A)-selected RNA from infected cells or relied solely on annotated host protein-coding genes to define host mRNAs selected by the virus. To examine the substrate-product relationship between all host RNAs, including non-coding RNAs, and viral RNAs, we used an unbiased approach to identify the host and viral capped RNAs from IAV-infected cells. We demonstrate that IAV predominantly snatches caps from non-coding host RNAs, particularly U1 and U2 small nuclear RNAs (snRNAs). Because snRNAs regulate host mRNA processing, cap-snatching of snRNAs may constitute a means by which IAV hijacks host cell metabolism.
2015-11-23 | GSE67493 | GEO
Project description:Influenza A virus (IAV) is a major respiratory pathogen that causes severe illness and mortality worldwide. IAV critically depends on host factors for multiple functions that are not encoded by the viral genome. Notably, the IAV RNA-dependent RNA polymerase (RdRP) complex lacks intrinsic 7-methylguanosine (m7G) capping activity and instead “snatches” the 5’m7G caps and the adjacent 10-15nts of host transcripts to prime viral mRNA production, allowing viral transcripts to be recognized by the host translation machinery. We developed a new approach to simultaneously assay the 5’ ends of host and viral transcripts in infected cells and identify the host capsnatch origins for viral mRNAs. We used this technique to study the progression of IAV infection in nuclear and cytoplasmic compartiments and determined that the RdRP complex has specific sequence preferences that results in preferential capsnatching and avoidance of sub-populations of host RNAs, which can be reverted by the addition of a cap-snatch inhibitor. Notably, genes avoided by CapSnatch Seq have biological functions enriched for mRNA processing, translation, and viral replication. This selectivity and functional enrichment of avoided genes is conserved among capsnatching viruses including Influenza B Virus and Lymphocytic Choriomeningitis Virus, despite differences in RdRP domains and subcellular locations of RNA substrates. This suggests that this preference convergently arose as a viral strategy to allow cap-snatching viruses to avoid targeting genes necessary for its own replication.
2017-08-09 | GSE85474 | GEO
Project description:Influenza A virus (IAV) is a threat to mankind because it generates yearly epidemics and poorly predictable sporadic pandemics with catastrophic potential. Influenza has a small RNA genome (~14 Kb) composed of 8 mini-chromosomes (segments). Segments encode both structural proteins and proteins expressed only during infection. Segments are constituted by a 5’UTR followed by a coding region and a 3’UTR. Transcription of IAV RNA into mRNA depends on host RNA Polymerase II, as the viral polymerase cleaves 5’ capped cellular nascent transcripts to be used as primers to initiate mRNA synthesis. We hypothesized that host nascent transcripts bearing AUG could generate upstream ORFs in the viral segments, a phenomenon that would depend on the translatability of the viral 5’UTRs. Using orthogonal datasets we report the existence of this mechanism, which generate host-virus chimeric proteins. We show that most segments encode proteins in this manner, expanding the proteome diversity of IAV in infected cells. Host-virus chimeric proteins are conserved across IAV strains, pointing to an evolutionary conservation of function achieved by sampling of the evolutionary space before gene fixation. Thus, we discover a mechanism that generate human-virus chimeric proteins during infection.
2020-06-25 | GSE128519 | GEO
Project description:Negative-sense RNA viruses (NSVs) rely on prepackaged viral RNA-dependent RNA polymerases (RdRp) to replicate and transcribe their viral genomes. Their replication machinery consists of an RdRp bound to viral RNA which is wound around a nucleoprotein (NP) scaffold, forming a viral ribonucleoprotein complex. NSV NP is known to regulate transcription and replication of genomic RNA, however its role in maintaining and protecting the viral genetic material is unknown. Here, we exploited host microRNA expression to target NP of influenza A virus and Sendai virus to ascertain how this would impact genomic levels and the host response to infection. We find that in addition to inducing a drastic decrease in genome replication, the antiviral host response in the absence of NP is dramatically enhanced. Additionally, our data shows that insufficient levels of NP prevent the replication machinery of these NSVs to process full-length genomes, resulting in aberrant replication products which form pathogen-associated molecular patterns in the process. These dynamics facilitate immune recognition by cellular pattern recognition receptors leading to a strong host antiviral response. Moreover, we observe that the consequences of limiting NP levels are universal amongst NSVs including Ebola virus, Lassa virus and Measles virus. Overall, these results provide new insights into viral genome replication of negative-sense RNA viruses and highlight novel avenues towards developing effective antiviral strategies, adjuvants, and/or live-attenuated vaccines.
2021-02-02 | GSE165340 | GEO
Project description:Influenza A virus (IAV) is a human respiratory pathogen that causes yearly global epidemics, and sporadic pandemics due to human adaptation of pathogenic strains. Efficient replication of IAV in different species is, in part, dictated by its ability to exploit the genetic environment of the host cell. To investigate IAV tropism in human cells, we evaluated the replication of IAV strains in a diverse subset of epithelial cell lines. HeLa cells were refractory to growth of human H1N1 and H3N2, and low pathogenic avian influenza (LPAIs) viruses. Interestingly, a human isolate of the highly pathogenic avian influenza (HPAI) virus H5N1 successfully propagated in HeLa cells to levels comparable to a human lung cell line. Heterokaryon cells generated by fusion of HeLa and permissive cells supported H1N1 growth, suggesting the absence of a host factor(s) required for replication of H1N1, but not H5N1, in HeLa cells. The absence of this factor(s) was mapped to reduced nuclear import, replication, and translation, and deficient viral budding. Using reassortant H1N1:H5N1 viruses, we found that the combined introduction of nucleoprotein (NP) and hemagglutinin (HA) from H5N1 was necessary and sufficient to enable H1N1 growth. Overall, this study suggests the absence of one or more cellular factors in HeLa cells that results in abortive replication of H1N1, H3N2, and LPAI viruses, but can be circumvented upon introduction of H5N1 NP and HA. Further understanding of the molecular basis of this restriction will provide important insights into virus-host interactions that underlie IAV pathogenesis and tropism.
2019-11-21 | GSE140759 | GEO
Project description:Virus infection may shut off host protein synthesis in order to achieve the replicative advantage over host cells. It is well known that human pathogenic viruses, particularly the picornaviruses, can block host protein synthesis by cleavage or inhibition of eukaryotic initiation factors (eIFs). In this study we found a novel mechanism that microRNA (miRNA) is involved in viral pathogenesis. Infection of enteroviruses can disturb the expression of host miRNAs, in which miR-141 is up-regulated and inhibits host protein synthesis by post-transcriptional repression of the target gene eIF4E, a key element for cap-dependent translation of host proteins. Knockdown of miR-141 by a specific siRNA, antagomiR-141, could restore host eIF4E expression, delay the occurrence of cytopathic effect (CPE), and impair virus propagation. We demonstrated that EV71 infection could increase early growth response 1 (EGR1) expression which induced miR-141 causing the eIF4E suppression; while silencing of EGR1 attenuated virus production. Our results suggest that enterovirus infection causes the EGR1-mediated upregulation of host miR-141, further lead to the translational switch from cap-dependent to cap-independent protein synthesis in the host cells, an environmental beneficial for viral propagation. This novel mechanism may highlight a new approach for future development of antiviral therapy. Enteroviruses in the Picornaviridae family are important human pathogens which can cause fatal diseases, including cardiopulmonary failure, aseptic meningitis, paralysis, myocarditis, and encephalomyelitis. Virus infection may induce shutoff of host protein synthesis, particularly in picornavirus, whose protein translation is cap-independent. It is known that poliovirus 2A protease cleaves eIF4G, a scaffold component of mammalian cell translational complex, leading to the shut down of host protein synthesis. Nevertheless, the cleavage of eIF4G may not be sufficient for the complete shutoff of host protein synthesis. Previous studies showed that cleavage of polyA-binding protein (PABP) by viral protease 3C and dephosphorylation of the translational repressor, eIF4E binding protein 1 (4E-BP1), also contribute to this process. The cap-binding protein, eIF4E, is the most crucial factor in determining whether cap-dependent or -independent translation takes place. The mechanism by which viral infection modulates host cell protein synthesis through interfering eIF4E expression is not yet known. miRNAs are a newly discovered class of small non-protein-coding RNAs that may act via endogenous RNA interference. Our understanding of its role in the dynamic interplay between virus and host components is quite limited. Since both virus infection and miRNAs could hinder cellular protein synthesis, whether miRNAs are involved during virus infection in shutting off host protein synthesis is still unknown. To address this issue, we analyze the altered gene and microRNA expression after EV71 infection. ***This submission represents the mRNA expression component of the study only***
2011-01-03 | E-GEOD-15323 | biostudies-arrayexpress
Project description:The influenza polymerase cleaves host RNAs ~10–13 nucleotides downstream of their 5′ ends and uses this capped fragment to prime viral mRNA synthesis. To better understand this process of cap snatching, we used high-throughput sequencing to determine the 5′ ends of A/WSN/33 (H1N1) influenza mRNAs. The sequences provided clear evidence for nascent-chain realignment during transcription initiation and revealed a strong influence of the viral template on the frequency of realignment. After accounting for the extra nucleotides inserted through realignment, analysis of the capped fragments indicated that the different viral mRNAs were each prepended with a common set of sequences and that the polymerase often cleaved host RNAs after a purine and often primed transcription on a single base pair to either the terminal or penultimate residue of the viral template. We also developed a bioinformatic approach to identify the targeted host transcripts despite limited information content within snatched fragments and found that small nuclear RNAs and small nucleolar RNAs contributed the most abundant capped leaders. These results provide insight into the mechanism of viral transcription initiation and reveal the diversity of the cap-snatched repertoire, showing that noncoding transcripts as well as mRNAs are used to make influenza mRNAs. Sixteen datasets were generated, corresponding to template-switching 5’-RACE libraries of 1) each viral RNA, 2) a time-course of NS1 viral RNA, or 3) CIP-TAP libraries of NS1 and PB2. Libraries contain random barcodes of length 5 (NS1_TS, PB2_TS, NS1_5R, PB2_5R) or 9 (other datasets) at the start of each read, and at least three guanosine residues for the template-switching datasets. See methods of accompanying paper for further details. Samples were sequenced on an Illumina HiSeq 2000.
2015-04-23 | E-GEOD-65101 | biostudies-arrayexpress
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