Profiling the small RNAs plasma levels in KSHV-infected Ugandan patients without KS
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ABSTRACT:
INSTRUMENT(S):
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Blood Plasma
SUBMITTER: 
Qing Zhang
LAB HEAD: Serge Barcy, PhD
PROVIDER: PXD008107 | Pride | 2018-02-16
REPOSITORIES: Pride
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Project description:Primary effusion lymphoma (PEL) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) and frequently also harbors Epstein-Barr virus (EBV). The expression of KSHV- and, often, EBV-encoded microRNAs (miRNAs) in PELs suggests a role for these miRNAs in viral latency and lymphomagenesis. Here we report the direct and transcriptome-wide identification of miRNA target sites for all miRNAs expressed in PEL cell lines. The resulting dataset revealed that KSHV miRNAs directly target more than 2000 cellular mRNAs encoding proteins that function in pathways with relevance to KSHV pathogenesis. Moreover, ~50% of these mRNAs are also targeted by EBV miRNAs, via distinct binding sites. In addition to a known viral analog of miR-155, we show that KSHV encodes a viral miRNA that mimics cellular miR-142-3p function. In summary, these experiments identify an extensive list of mRNAs targeted by KSHV miRNAs and indicate that these are likely to strongly influence viral replication and pathogenesis. small RNA sequencing, 3 samples Ago2 (EIF2C2) PAR-CLIP, 2 samples
2011-11-16 | E-GEOD-32109 | biostudies-arrayexpress
Project description:Primary effusion lymphoma (PEL) is caused by Kaposi's sarcoma-associated herpesvirus (KSHV) and frequently also harbors Epstein-Barr virus (EBV). The expression of KSHV- and, often, EBV-encoded microRNAs (miRNAs) in PELs suggests a role for these miRNAs in viral latency and lymphomagenesis. Here we report the direct and transcriptome-wide identification of miRNA target sites for all miRNAs expressed in PEL cell lines. The resulting dataset revealed that KSHV miRNAs directly target more than 2000 cellular mRNAs encoding proteins that function in pathways with relevance to KSHV pathogenesis. Moreover, ~50% of these mRNAs are also targeted by EBV miRNAs, via distinct binding sites. In addition to a known viral analog of miR-155, we show that KSHV encodes a viral miRNA that mimics cellular miR-142-3p function. In summary, these experiments identify an extensive list of mRNAs targeted by KSHV miRNAs and indicate that these are likely to strongly influence viral replication and pathogenesis.
2011-11-16 | GSE32109 | GEO
Project description:The nucleus is a highly structured environment containing multiple membrane-less bodies formed through liquid-liquid phase separation. These provide spatial separation and concentration of specific biomolecules enabling efficient and discrete processes to occur which regulate gene expression. One such nuclear body, paraspeckles, are comprised of multiple paraspeckle proteins (PSPs) built around the architectural RNA, NEAT1_2. Paraspeckle function is yet to be fully elucidated but has been implicated in a variety of developmental and disease scenarios. We demonstrate that Kaposi’s sarcoma-associated herpesvirus (KSHV) drives formation of structurally distinct paraspeckles with a dramatically increased size and altered protein composition that are essential for productive lytic replication. We highlight these virus-induced paraspeckle-like structures form adjacent to virus replication centres, functioning as RNA processing hubs for both viral and cellular transcripts during infection. Notably, we reveal that PSP sequestration into virus-induced paraspeckle-like structures results in increased genome instability during both KSHV and Epstein Barr virus (EBV) infection, implicating their formation in virus-mediated tumorigenesis.
2024-11-04 | PXD048834 | Pride
Project description:Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphoma (PEL). All PEL cell lines are infected with KSHV, and 70% are co-infected with Epstein-Barr Virus (EBV). KSHV reactivation from latency requires promoter-specific transactivation by the KSHV Rta protein through interactions with RBP-Jk (CSL), the cellular DNA binding component of the Notch signal transduction pathway. EBV transformation of primary B cells requires EBV nuclear antigen (EBNA)-2 to interact with RBP-Jk to direct the latent viral and cellular gene expression program. Although KSHV Rta and EBV EBNA-2 both require RBP-Jk for transactivation, previous studies have suggested that RBP-Jk-dependent transactivators do not function identically. We have found that the EBV latent protein LMP-1 is expressed in less than 5% of KSHV+/EBV+ PEL cells, but is induced in an Rta-dependent fashion when KSHV reactivates. KSHV Rta transactivates the EBV latency promoters in an RBP-Jk-dependent fashion and forms a ternary complex with RBP-Jk on the promoters. In B cells that are conditionally transformed by EBV alone, we show that KSHV Rta complements a short-term EBNA2 growth deficiency in an autocrine/paracrine manner. Complementaton of EBNA2-deficiency by Rta depends on RBP-Jk and LMP-1, and Rta transactivation is required for optimal growth of KSHV+/EBV+ PEL lines. Our data suggest that Rta can contribute to EBV-driven cellular growth by transactivating RBP-Jk-dependent EBV latency genes. However, our data also suggest that EBNA2 and Rta induce distinct alterations in the cellular proteomes that contribute to growth of infected cells.
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Project description:We previously demonstrated that 25HC (25-hydroxycholesterol, a derivative of cholesterol) blocks KSHV (Kaposi Sarcoma-associated Herpesvirus/ Human Herpesvirus-8) de novo infection of primary endothelial cells at a post-entry step and decreases viral gene expression. Herein we sought to determine transcriptomic changes associated with 25HC treatment of primary endothelial cells and primary B cells using RNA sequencing. To understand how 25HC inhibits KSHV infection, we examined global gene expression changes induced by 25HC in HUVECs, with or without KSHV infection. We pre-treated HUVEC with 25HC or vehicle control, then infected with KSHV (four conditions: -/+ 25HC, -/+ infection). At 2 days post-infection (dpi), we harvested RNA and performed RNA-seq to determine differentially expressed genes. We found that 25HC treatment inhibited KSHV gene expression globally and induced several inflammatory cytokines (CXCL8, IL1?), AP-1 components, and innate immunity receptors (RIG-I, TLR2) . Likewise, we also observed 25HC to block EBV de novo infection by inducing apoptosis and blocking transformation into lymphoblastoid cell lines. To determine transcriptomic changes that contributes to this, we purified B cells from healthy donors and infected them with EBV after 25HC pre-treatment with 4 similar conditions mentioned above. Samples were sent for RNA-Seq at 10-12 dpi. In contrast to KSHV infection, we found that only a subset of EBV viral transcripts are downregulated in the 25HC-treated samples. LMP1, which is the primary oncogenic factor, was suppressed and several downstream host targets that would prevent apoptosis during infection were likewise dysregulated. Additionally, several viral noncoding RNAs were also highly downregulated. Further analyses revealed that some 25HC-induced genes in our KSHV data set overlap with antiviral genes that were previously identified in various published screens involving other viruses, demonstrating the broad activity of 25HC. Together, these results answer some important questions about a widely acting antiviral (25HC), with implications for multiple viral and bacterial infections.
2021-11-24 | GSE165328 | GEO
Project description:Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphoma (PEL). All PEL cell lines are infected with KSHV, and 70% are co-infected with Epstein-Barr Virus (EBV). KSHV reactivation from latency requires promoter-specific transactivation by the KSHV Rta protein through interactions with RBP-Jk (CSL), the cellular DNA binding component of the Notch signal transduction pathway. EBV transformation of primary B cells requires EBV nuclear antigen (EBNA)-2 to interact with RBP-Jk to direct the latent viral and cellular gene expression program. Although KSHV Rta and EBV EBNA-2 both require RBP-Jk for transactivation, previous studies have suggested that RBP-Jk-dependent transactivators do not function identically. We have found that the EBV latent protein LMP-1 is expressed in less than 5% of KSHV+/EBV+ PEL cells, but is induced in an Rta-dependent fashion when KSHV reactivates. KSHV Rta transactivates the EBV latency promoters in an RBP-Jk-dependent fashion and forms a ternary complex with RBP-Jk on the promoters. In B cells that are conditionally transformed by EBV alone, we show that KSHV Rta complements a short-term EBNA2 growth deficiency in an autocrine/paracrine manner. Complementaton of EBNA2-deficiency by Rta depends on RBP-Jk and LMP-1, and Rta transactivation is required for optimal growth of KSHV+/EBV+ PEL lines. Our data suggest that Rta can contribute to EBV-driven cellular growth by transactivating RBP-Jk-dependent EBV latency genes. However, our data also suggest that EBNA2 and Rta induce distinct alterations in the cellular proteomes that contribute to growth of infected cells. EREB2-5 cells were transfected and grown in the presence or absence of β-estradiol, as described. Seven days post-transfection, protein extracts were prepared, and 200 ugs. of each were analyzed using the RayBio Human Apoptosis Antibody Array Kit (RayBiotech) as per manufacturers suggestions. The membranes were exposed to autoradiography film for different times to detect the chemiluminescent signals. Images with signals in linear range were quantitated using the program ImageJ [59]. For each membrane, signals from the negative control spots were averaged, and then subtracted from each of the other spots. A signal was considered valid if its value exceeded both its average local background, and the average of all valid negative control values. Valid signals were normalized using the positive control spots (for cellular BID protein). Fold change in signals for each spot were quantitated by dividing by the valid signals for each corresponding spot on the minus β-estradiol membrane. Average fold change, and standard deviation, were calculated for each protein.
2010-12-31 | E-GEOD-21375 | biostudies-arrayexpress
Project description:Cancer cells of primary effusion lymphoma (PEL) often contain both Kaposi sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV). We measured the interplay of human, KSHV, and EBV transcription in a cell culture model of PEL using single-cell RNA sequencing. The data detect widespread trace expression of lytic KSHV genes.
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Project description:Primary effusion lymphomas (PELs) are specifically associated with KSHV/HHV-8 infection, and most frequently occur in HIV-positive individuals as lymphomatous effusions in the serous cavities without a detectable solid tumor mass. Most PELs have concomitant EBV infection, suggesting that EBV is an important pathogenetic co-factor, although other as yet unidentified cofactors, such as cellular genetic alterations, are also likely to play a role. Lymphomatous effusions that lack KSHV also occur; these are frequently EBV-associated in the setting of HIV infection. Here we used gene expression profile analysis to determine the viral impact on cellular gene expression and the pathogenesis of these lymphomatous effusions. We used the Affymetrix HG-U133A microarray to analyze the gene expression profile of these effusion lymphomas (three virologic groups: KSHV-positive EBV-positive PELs, KSHV-positive EBV-negative PELs and KSHV-negative EBV-positive lymphomatous effusions). Nine cell lines derived from patients with lymphomatous effusions (three from each virologic group and each cell line was done in duplicates.) and three PEL patient samples were used in the study. Our results suggest that KSHV-positive PELs are very different from KSHV-negative lymphomatous effusions, and the genes that are differentially expressed include apoptosis regulators, cell cycle regulators, transcriptional factors and signal transduction regulators. KSHV clearly plays a dominant role in the phenotype of PEL. Within the KSHV-positive PELs, two subgroups can be identified, which were correlated with their EBV viral status. Among these genes (45 gene probes), four were regulators of the MAP kinase pathway that were up-regulated in the KSHV-positive, EBV-negative PELs, suggesting that in the absence of EBV, events that lead to the activation of the MAP kinase pathway may act as a cofactor for the development of PEL. Next we determined whether we could predict the viral status of the three primary patient cases of PEL based on the 45 gene probes that were differentially expressed in KSHV-positive cell lines according to EBV status (pt. 1: KSHV-positive, EBV-positive; Pt. 2: KSHV-positive, low proportion of EBV-positive; pt. 3: KSHV-positive EBV-negative), and we could.<br><br>Samples:<br>KSHV-positive EBV-positive cell lines: BC-1, BC-2, BC-5 <br>KSHV-positive EBV-negative cell lines: BC-3, BCBL-1, PEL-5 <br>KSHV-negative EBV-positive cell lines: IBL4, SM1, BCKN-1 <br>Patient 1: KSHV-positive, EBV-positive <br>Patient 2: KSHV-positive, EBV-positive (low number of positive cells) <br>Patient 3: KSHV-positive, EBV-negative.
2007-08-25 | E-GEOD-2149 | biostudies-arrayexpress
Project description:Primary effusion lymphomas (PELs) are specifically associated with KSHV/HHV-8 infection, and most frequently occur in HIV-positive individuals as lymphomatous effusions in the serous cavities without a detectable solid tumor mass. Most PELs have concomitant EBV infection, suggesting that EBV is an important pathogenetic co-factor, although other as yet unidentified cofactors, such as cellular genetic alterations, are also likely to play a role. Lymphomatous effusions that lack KSHV also occur; these are frequently EBV-associated in the setting of HIV infection. Here we used gene expression profile analysis to determine the viral impact on cellular gene expression and the pathogenesis of these lymphomatous effusions. We used the Affymetrix HG-U133A microarray to analyze the gene expression profile of these effusion lymphomas (three virologic groups: KSHV-positive EBV-positive PELs, KSHV-positive EBV-negative PELs and KSHV-negative EBV-positive lymphomatous effusions). Nine cell lines derived from patients with lymphomatous effusions (three from each virologic group and each cell line was done in duplicates.) and three PEL patient samples were used in the study. Our results suggest that KSHV-positive PELs are very different from KSHV-negative lymphomatous effusions, and the genes that are differentially expressed include apoptosis regulators, cell cycle regulators, transcriptional factors and signal transduction regulators. KSHV clearly plays a dominant role in the phenotype of PEL. Within the KSHV-positive PELs, two subgroups can be identified, which were correlated with their EBV viral status. Among these genes (45 gene probes), four were regulators of the MAP kinase pathway that were up-regulated in the KSHV-positive, EBV-negative PELs, suggesting that in the absence of EBV, events that lead to the activation of the MAP kinase pathway may act as a cofactor for the development of PEL. Next we determined whether we could predict the viral status of the three primary patient cases of PEL based on the 45 gene probes that were differentially expressed in KSHV-positive cell lines according to EBV status (pt. 1: KSHV-positive, EBV-positive; Pt. 2: KSHV-positive, low proportion of EBV-positive; pt. 3: KSHV-positive EBV-negative), and we could. Samples: KSHV-positive EBV-positive cell lines: BC-1, BC-2, BC-5 KSHV-positive EBV-negative cell lines: BC-3, BCBL-1, PEL-5 KSHV-negative EBV-positive cell lines: IBL4, SM1, BCKN-1 pt. 1: KSHV-positive, EBV-positive pt. 2: KSHV-positive, EBV-positive (low number of positive cells) pt. 3: KSHV-positive, EBV-negative Keywords: other
2005-01-16 | GSE2149 | GEO
Project description:Epstein-Barr virus (EBV) and Kaposi’s sarcoma herpesvirus (KSHV) cause ~2% of all human cancers. RNase R-resistant RNA sequencing revealed that both gammaherpesviruses encode multiple, uniquely stable, circular RNAs (circRNA). EBV abundantly expressed both exon-only and exon-intron circRNAs from the BART locus (circBARTs) formed from a spliced BART transcript and excluding the EBV miRNA region. CircBARTs were expressed in all verified EBV latency types, including EBV- positive post-transplant lymphoproliferative disease (PTLD), Burkitt lymphoma, nasopharyngeal carcinoma, and AIDS-associated lymphoma tissues and cell lines. Only cells infected with the B95-8 EBV strain, with a 12-kb BART locus deletion, were negative for EBV circBARTs. Less abundant levels of EBV circRNAs originating from LMP2 and BHLF1-encoding genes were also identified. CircRNA sequencing of KSHV- infected PEL cells revealed a KSHV-encoded circRNA from the vIRF4 locus (circvIRF4) that was constitutively expressed. In addition, KSHV polyadenylated nuclear (PAN) RNA locus generated a swarm (>100) of multiply backspliced, low-abundance RNase R- resistant circRNAs originating in both sense and antisense directions consistent with a novel hyper-backsplicing mechanism. In EBV and KSHV co-infected cells, exon-only EBV circBARTS were located more in the cytoplasm, whereas the intron-retaining circBARTs were found in the nuclear fraction. KSHV circvIRF4 and circPANs were detected in both nuclear and cytoplasmic fractions. Among viral circRNAs tested, none were found in polysome fractions from KSHV-EBV co-infected BC1 cells although low abundance protein translation from viral circRNAs could not be excluded. CircRNAs are a new class of viral transcripts expressed in gammaherpesvirus-related tumors that might contribute to viral oncogenesis.
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