Integrated Systems Biology Analysis of KSHV Latent Infection Reveals Viral Induction and Reliance on Peroxisome Mediated Lipid Metabolism
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE84237 | GEO | 2017/02/08
SECONDARY ACCESSION(S): PRJNA328457
REPOSITORIES: GEO
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Project description:Deregulation of host lncRNAs following infection with Kaposi’s sarcoma-associated herpesvirus (KSHV) was assessed. Total RNA was prepared from uninfected TIVE cells (telomerase-immortalized vein endothelial cells), and from TIVE cells latently infected with either wild-type KSHV or with a deletion mutant (Δcluster-KSHV) lacking ten of the twelve KSHV microRNA genes. The RNA was converted to labeled cRNA and used to probe a human lncRNA microarray. The goal was to investigate which host lncRNAs were either up- or down-regulated during latent infection with KSHV, and to determine if deregulation of host lncRNAs was dependent on KSHV miRNAs.
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Project description:Kaposi’s Sarcoma associated herpesvirus (KSHV) is an oncogenic human virus and leading cause of mortality in HIV infection. Reactivation of KSHV from latent to lytic stage infection initiates a cascade of viral gene expression, and here we show how these changes remodel the host cell proteome to enable viral replication. By undertaking a systematic and unbiased analysis of changes to the endothelial cell proteome following lytic KSHV reactivation, we quantify >7000 cellular and 71 viral proteins. Lytic KSHV infection resulted in >2-fold downregulation of 291 cellular proteins, including PKR, the key cellular sensor of double-stranded RNA. A complementary KSHV genome-wide CRISPR genetic screen identified K5 as the viral gene responsible for the downregulation of two novel KSHV targets, Nectin-2 and CD155, both ligands of the NK cell DNAM-1 receptor. Despite the high episome copy number, we show that CRISPR Cas9 provides a remarkably efficient way to target KSHV genomes.
2021-08-23 | PXD021387 | Pride
Project description:Kaposi’s Sarcoma associated herpesvirus (KSHV) is an oncogenic human virus and leading cause of mortality in HIV infection. Reactivation of KSHV from latent to lytic stage infection initiates a cascade of viral gene expression, and here we show how these changes remodel the host cell proteome to enable viral replication. By undertaking a systematic and unbiased analysis of changes to the endothelial cell proteome following lytic KSHV reactivation, we quantify >7000 cellular and 71 viral proteins. Lytic KSHV infection resulted in >2-fold downregulation of 291 cellular proteins, including PKR, the key cellular sensor of double-stranded RNA. A complementary KSHV genome-wide CRISPR genetic screen identified K5 as the viral gene responsible for the downregulation of two novel KSHV targets, Nectin-2 and CD155, both ligands of the NK cell DNAM-1 receptor. Despite the high episome copy number, we show that CRISPR Cas9 provides a remarkably efficient way to target KSHV genomes.
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Project description:The epitranscriptomic modification m6A is a ubiquitous feature of the mammalian transcriptome. It modulates mRNA fate and dynamics to exert regulatory control over numerous cellular processes and disease pathways, including viral infection. Kaposi’s sarcoma-associated herpesvirus (KSHV) reactivation from the latent phase leads to redistribution of m6A topology upon both viral and cellular mRNAs within infected cells. Here we investigate the role of m6A in cellular transcripts upregulated during KSHV lytic replication. Results show that m6A is crucial for the stability of the GPRC5A mRNA, whose expression is induced by the KSHV latent-lytic switch master regulator, the replication and transcription activator (RTA) protein. Moreover, we demonstrate that GPRC5A is essential for efficient KSHV lytic replication by directly regulating NFκB signalling. Overall, this work highlights the central importance of m6A in modulating cellular gene expression to influence viral infection.
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Project description:Gammaherpesviruses, including the human pathogens Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus, establish lifelong latent infection in B cells and are associated with a variety of tumors. In addition to protein coding genes, these viruses encode numerous microRNAs (miRNAs) within their genomes. While putative host targets of EBV and KSHV miRNAs have been previously identified, the specific functions of these miRNAs during in vivo infection are largely unknown. Murine gammaherpesvirus 68 is a natural pathogen of rodents that is genetically related to both EBV and KSHV, and thus serves as an excellent model for the study of EBV and KSHV elements such as miRNAs in the context of infection and disease. However, MHV68 the specific targets of miRNAs remain unknown. Using a technique known as quick CLASH (crosslinking, ligation, and sequencing of hybrids), we have now identified specific, Ago-associated mRNA targets of MHV68 miRNAs during lytic infection, latent infection and reactivation from latency.
2019-05-27 | GSE124687 | GEO
Project description:We have reported that KSHV infection reprograms oral mesenchymal stem cells (MSCs) and transforms them to Kaposi sarcoma-like cells through mesenchymal-to-endothelial transition. To explore the mechanism of KSHV infection of MSCs, we compared the gene expression profiles of Kaposi’s sarcoma tissue and KSHV non-susceptible cells to explore potential host factors that contribute to KSHV infection.
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Project description:Abstract: The Kaposi’s sarcoma-associated herpesvirus (KSHV) is an important oncogenic virus previously shown to be neurotropic, but studies on neuronal cells infection and pathogenesis are still very limited. Here we characterized the effects of KSHV infection on neuronal SH-SY5Y cells by the recombinant virus rKSHV219, which expresses both GFP and RFP to reflect latent and lytic phases of infection. We demonstrated that infected cells have a faster growth rate and the KSHV infection can be sustained. Interestingly, the infected cells can transition spontaneously back and forth between lytic and latent phases of infections, producing progeny viruses but without any adverse effects on cell growth. In addition, transcriptome analysis of viral and cellular genes in latent and lytic cells showed that unlike other infected cell lines, the latently infected cells expressed both latent and most, but not all the lytic genes required for infectious virion production. The uniquely expressed viral genes by the lytic cells were mainly involved in the early steps of virus binding. Some of the cellular genes that were deregulated in both latent and lytically infected cells are involved in cell adhesion, in cell signal pathways and tumorigenesis. The downregulated cellular CCDN1, PAX5, NFASC and upregulated CTGF, BMP4, YAP1, LEF1 and HLA-DRB1 genes were found to be associated with the cell adhesion molecules (CAM), hippo signaling and cancer. These deregulated genes may be involved in creating an environment that are unique in the neuronal cells to sustain cell growth upon KSHV infection not observed in other infected cell types. IMPORTANCE: Our study has provided evidence that the neuronal SH-SY5Y cells displayed unique cellular responses upon KSHV infection. Unlike other infected cells, this neuronal cell displayed a more rapid growth rate upon infection and can spontaneously transition back and forth between latent and lytic phases of infection. Unlike other latently infected cells, a number of lytic genes were also expressed in the latent phase of infection in addition to the established latent viral genes. They may play a role in deregulating a number of host genes that are involved in cell signaling and tumorigenesis in order to sustain the infection and growth advantages for the cells. Our study has provided novel insights on KSHV infection of neuronal cells and a potential new model for further studies to explore the underlying mechanism in viral and host interaction for neuronal cells, and the association of KSHV with neuronal diseases.
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Project description:Kaposi’s sarcoma-associated herpesvirus (KSHV) is a g-herpesvirus which persists as circular extrachromasomal DNA in the nucleus during latent infection. During latency a limited number of viral proteins are expressed, including LANA (latency-associated nuclear antigen). LANA is a multi-functional protein known to interact with transcriptional regulators and chromatin remodelers, and to regulate the LANA and RTA promoters. We hypothesized that LANA may contribute to the establishment of latency through controlling chromatinization and histone modification of KSHV episomes. We performed ChIP-seq analysis and correlated H3K4me3, H3K27me3, polII, and LANA occupancy of the KSHV genome at nucleotide resolution. Epigenetic marks were analyzed in BCBL-1 lymphoid cells and in telomerase-immortalized vein endothelial TIVE-LTC cells. We found that the transcription active mark H3K4me3, but not silencing mark H3K27me3, was enriched at KSHV regions where LANA is bound. Co-occupancy of LANA and H3K4 was also detected on 167 host genes, of which 89 are actively transcribed. By comparing LANA occupancy with the profiling of 43 transcription factors from ENCODE, a subset of transcription factors was enriched at regions where LANA is bound, including znf143, CTCF, and Stat1. These results indicate that LANA also plays a role in modulating expression of host genes. Co-immunoprecipitation of LANA with the H3K4 methyltransferase hSET1 suggests that LANA recruits hSET1 to specific loci on the viral genome, leading to H3K4 methylation and ensuring transcription of latency-associated genes. Host gene expression may be regulated by the same mechanism. LANA binding was correlated with the distribution in the latent KSHV genome of the transcription active histone modification H3K4me3, the silencing mark H3K27me3, and RNA polymerase II, using cells of lymphoid and endothelial origin. A similar analysis was done for the human genome. Biological replicates (BR) and technical replicates (TR) were included.
2014-10-27 | E-GEOD-52421 | biostudies-arrayexpress
Project description:Historically, ribosomes have been viewed as unchanged homogeneous macromolecular machines with no intrinsic regulatory capacity for mRNA translation. However, an emerging concept is that heterogeneity of ribosomal composition exists, which can exert a regulatory function or specificity in translational control. This is supported by recent discoveries identifying compositionally distinct ‘specialised ribosomes’ that actively regulate mRNA translation. Viruses lack their own translational machinery and impose a high translational demand on the host cell during replication. Here we explore the possibility that Kaposi’s sarcoma-associated herpesvirus (KSHV) can manipulate host ribosome biogenesis during infection to produce specialised ribosomes which preferentially translate viral transcripts. Quantitative proteomic analysis has identified changes in the stoichiometry and composition of precursor ribosomal complexes during the switch from latent to lytic KSHV replication. Intriguingly, we demonstrate the enhanced association of ribosomal biogenesis factors BUD23 and NOC4L, and a previously uncharacterised KSHV lytic protein, ORF11, with small ribosomal subunit precursor complexes during lytic KSHV infection. Notably, BUD23 depletion resulted in significantly reduced viral gene expression and progression through the lytic cascade, culminating in a dramatic reduction of infectious virion production. Importantly, ribosome profiling demonstrated that BUD23 is essential for the reduced association of ribosomes with KSHV uORFs in late lytic genes, required for the efficient translation of the main open reading frame. Together our results provide new mechanistic insights into KSHV-mediated manipulation of cellular ribosome composition inducing a population of specialised ribosomes to facilitate efficient translation of viral mRNAs.
2022-12-21 | PXD032367 | Pride
Project description:Historically, ribosomes have been viewed as unchanged homogeneous macromolecular machines with no intrinsic regulatory capacity for mRNA translation. However, an emerging concept is that heterogeneity of ribosomal composition exists, which can exert a regulatory function or specificity in translational control. This is supported by recent discoveries identifying compositionally distinct ‘specialised ribosomes’ that actively regulate mRNA translation. Viruses lack their own translational machinery and impose a high translational demand on the host cell during replication. Here we explore the possibility that Kaposi’s sarcoma-associated herpesvirus (KSHV) can manipulate host ribosome biogenesis during infection to produce specialised ribosomes which preferentially translate viral transcripts. Quantitative proteomic analysis has identified changes in the stoichiometry and composition of precursor ribosomal complexes during the switch from latent to lytic KSHV replication. Intriguingly, we demonstrate the enhanced association of ribosomal biogenesis factors BUD23 and NOC4L, and a previously uncharacterised KSHV lytic protein, ORF11, with small ribosomal subunit precursor complexes during lytic KSHV infection. Notably, BUD23 depletion resulted in significantly reduced viral gene expression and progression through the lytic cascade, culminating in a dramatic reduction of infectious virion production. Importantly, ribosome profiling demonstrated that BUD23 is essential for the reduced association of ribosomes with KSHV uORFs in late lytic genes, required for the efficient translation of the main open reading frame. Together our results provide new mechanistic insights into KSHV-mediated manipulation of cellular ribosome composition inducing a population of specialised ribosomes to facilitate efficient translation of viral mRNAs.
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