Epstein-Barr virus reactivation induces divergent abortive, reprogrammed, and host shutoff states by lytic progression
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ABSTRACT:
PROVIDER: PRJNA1138692 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR29914400.fastq.gz | Fastqsanger.gz | |||
| SRR29914401.fastq.gz | Fastqsanger.gz | |||
| SRR29914402.fastq.gz | Fastqsanger.gz | |||
| SRR29914403.fastq.gz | Fastqsanger.gz | |||
| SRR29914404.fastq.gz | Fastqsanger.gz |
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Project description:Viral infection leads to heterogeneous cellular outcomes ranging from resistance to virion amplification and cell death. In this study, we apply single-cell techniques to analyze diverse fate trajectories during Epstein-Barr virus (EBV) lytic reactivation in three B cell models. We expand upon the previous finding that c-Myc regulates lytic reactivation and determine that MYC downregulation during the lytic phase is correlated with a loss of germinal center (GC) B cell expression signatures. Consistent with prior work, lytic induction yields both abortive and complete reactivation. Abortive lytic cells, which express high STAT3 and initiate but do not complete the lytic cycle, also upregulate NF-kB and IRF3 pathway target genes. Cells that proceeded through the full lytic cycle exhibited unexpected and striking expression of genes associated with cellular reprogramming, developmental progenitor phenotypes, and cytokine upregulation. Distinct subpopulations of lytic cells further displayed variable profiles for transcripts known to escape virus-mediated host shutoff. These data reveal previously unknown and promiscuous outcomes of lytic reactivation with broad implications for viral replication and EBV-associated oncogenesis.
2024-10-31 | GSE272763 | GEO
Project description:This study characterizes the effects of Epstein-Barr virus (EBV) reactivation on the host and virus transcriptomes. For this work, a dual-fluorescent lytic reporter (DFLR) EBV was constructed based on the M81 EBV strain and used to transform primary B cells into lymphoblastoid cell lines (LCL). Deposited here is RNA-seq data from these DFLR LCLs that were induced by BCR crosslinking and sorted into latent, early lytic, and late lytic fractions. All samples consist of 40,000 sorted cells and include equal quantities of ERCC spike-in RNAs for normalization. We also performed the same experimental approach on a second DFLR LCL in which the EBV BGLF5 host shutoff nuclease was deleted. This allowed us to define which changes in the transcriptome during EBV replication were due to BGLF5. This approach demonstrated extensive shutoff of host genes during EBV replication and, unexpectedly, revealed that most of those changes were independent of BGLF5.
2024-07-08 | GSE271717 | GEO
Project description:We used microarrays to identify genes differentially expressed in EBV-infected human B cells supporting lytic replication vs. those refractory to EBV lytic replication. We used serum from EBV-positive subject (compared to serum from EBV-negative subject) to FACS-separate lytic and refractory cells following treatment of HH514-16 cells with NaB, a lytic cycle inducing agent. RNA from sorted-lytic and sorted-refractory cells were hybridized to microarray.
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Project description:Epstein-Barr virus (EBV) has a lifelong latency period after initial infection. Rarely, however, when the EBV immediate early gene BZLF1 is expressed by a specific stimulus, the virus switches to the lytic cycle to produce progeny viruses. We found that EBV infection reduced levels of various ceramide species in gastric cancer cells. As ceramide is a bioactive lipid implicated in the infection of various viruses, we assessed the effect of ceramide on the EBV lytic cycle. Treatment with C6-ceramide (C6-Cer) induced an increase in the endogenous ceramide pool and increased production of the viral product as well as BZLF1 expression. Treatment with the ceramidase inhibitor ceranib-2 induced EBV lytic replication with an increase in the endogenous ceramide pool. The glucosylceramide synthase inhibitor Genz-123346 inhibited C6-Cer-induced lytic replication. C6-Cer induced ERK1/2 and CREB phosphorylation, c-JUN expression, and accumulation of the autophagosome marker LC3B. Treatment with MEK1/2 inhibitor U0126 or autophagy initiation inhibitor 3-MA suppressed C6-Cer-induced EBV lytic replication. In contrast, the autophagosome-lysosome fusion inhibitor chloroquine induced BZLF1 expression. Transfection with siCREB reduced ERK1/2 phosphorylation and C6-Cer-induced BZLF1 expression. On the other hand, siJUN transfection did not affect BZLF1 expression. Our results show that increased endogenous ceramide and glycosyl ceramide (GlyCer) following C6-Cer treatment induce EBV lytic replication in gastric cancer cells via ERK1/2 and CREB phosphorylation and autophagosome accumulation.
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Project description:MYC controls Epstein Barr virus lytic switch
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Project description:Lytic activation from latency is a key transition point in the life cycle of herpesviruses. Epstein-Barr virus (EBV) is a human herpesvirus that can cause lymphomas, epithelial cancers, and other diseases, most of which require the lytic cycle. While the lytic cycle of EBV can be triggered by chemicals and immunologic ligands, the lytic cascade is only activated when expression of the EBV latency-to-lytic switch protein ZEBRA is turned on. ZEBRA then transcriptionally activates other EBV genes and together with some of those gene products ensures completion of the lytic cycle. However, not every latently-infected cell exposed to a lytic trigger turns expression of ZEBRA on, resulting in responsive and refractory subpopulations. What governs this dichotomy? By examining the nascent transcriptome following exposure to a lytic trigger, we find that several cellular genes are transcriptionally upregulated temporally upstream of ZEBRA. These genes regulate lytic susceptibility to variable degrees in latently-infected cells that respond to mechanistically distinct lytic triggers. While increased expression of these cellular genes defines a pro-lytic state, such upregulation also runs counter to the well-known mechanism of viral nuclease-mediated host shut-off that is activated downstream of ZEBRA. Furthermore, a subset of upregulated cellular genes is transcriptionally repressed downstream of ZEBRA, indicating an additional mode of virus-mediated host shut-off through transcriptional repression. Thus, increased transcription of a set of host genes contributes to a pro-lytic state that allows a subpopulation of cells to support the EBV lytic cycle.
2020-01-13 | GSE141220 | GEO
Project description:We used microarrays to identify genes differentially expressed in EBV-infected human B cells supporting lytic replication vs. those refractory to EBV lytic replication.
2013-08-21 | GSE49568 | GEO
Project description:Previously, we identified Syncytin1 to be expressed in human B cells and enhance EBV ability to undergo lytic replication. To gain mechanistic insight, we performed liquid chromatography tandem mass spectrometry (LC-MS/MS) on tryptic peptides from immunoprecipitated FLAG-tagged Syncytin-1 in latently infected EBV+ Burkitt lymphoma cells. This revealed a number of cellular proteins as potential Syncytin-1 interacting partners during latency and/or during the lytic phase as well as two EBV lytic phase proteins, the viral protein kinase and LF2, a negative regulator of EBV lytic gene transcription. We now find that Syncytin1 reduces the association between LF2 and the EBV replication and transcription activator to promote EBV lytic gene expression.
2023-05-15 | MSV000091949 | MassIVE
Project description:Viral infection induces dynamic changes in transcriptional profiles. Virus-induced and antiviral responses are intertwined during the infection. Epstein-Barr virus (EBV) is a human gammaherpesvirus that provides a model of herpesvirus latency. To measure the transcriptome changes during the establishment of EBV latency, we infected EBV-negative Akata cells with EBV-EGFP and performed transcriptome sequencing (RNA-seq) at 0, 2, 4, 7, 10, and 14 days after infection. We found transient downregulation of mitotic division-related genes, reflecting reprogramming of cell growth by EBV, and a burst of viral lytic gene expression in the early phase of infection. Experimental and mathematical investigations demonstrate that infectious virions were not produced in the pre-latent phase, suggesting the presence of an abortive lytic infection. Fate mapping using recombinant EBV provided direct evidence that the abortive lytic infection in the pre-latent phase converges to latent infection during EBV infection of B-cells, shedding light on novel roles of viral lytic gene(s) in establishing latency. Furthermore, we find that the BZLF1 protein, which is a key regulator of reactivation, was dispensable for abortive lytic infection in the pre-latent phase, suggesting the divergent regulation of viral gene expressions from a productive lytic infection.
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Project description:Epstein Barr virus (EBV) replication contributes to multiple human diseases, including infectious mononucleosis, nasopharyngeal carcinoma, B-cell lymphomas, and oral hairy leukoplakia. We performed systematic quantitative analyses of temporal changes in host and EBV proteins during lytic replication to gain novel insights into virus-host interactions, using conditional Burkitt lymphoma models of type I and II EBV infection. We quantified profiles of >8000 cellular and 69 EBV proteins, including >500 plasma membrane proteins, providing temporal views of the lytic B-cell proteome and EBV virome. Our approach revealed EBV-induced remodelling of cell cycle, innate and adaptive immune pathways, including upregulation of the complement cascade and proteasomal degradation of the B-cell receptor complex, conserved between EBV types I and II. Cross-comparison with proteomic analyses of human cytomegalovirus infection and of a Kaposi sarcoma associated herpesvirus immunoevasin identified host factors targeted by multiple herpesviruses. Our results provide an important resource for studies of EBV replication.
2017-05-19 | PXD006317 | Pride