Viral and host network analysis of the human cytomegalovirus transcriptome in latency
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ABSTRACT:
PROVIDER: PRJNA1108523 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28959800_1.fastq.gz | Fastqsanger.gz | |||
| SRR28959800_2.fastq.gz | Fastqsanger.gz | |||
| SRR28959801_1.fastq.gz | Fastqsanger.gz | |||
| SRR28959801_2.fastq.gz | Fastqsanger.gz | |||
| SRR28959802_1.fastq.gz | Fastqsanger.gz |
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Project description:Abstract: The transcriptional program associated with herpesvirus latency and the viral genes regulating entry into and exit from latency are poorly understood and controversial. Here, we developed and validated a targeted enrichment platform and conducted large-scale transcriptome analyses of human cytomegalovirus (HCMV) infection. We used both an experimental hematopoietic cell model of latency, and cells from naturally infected, healthy human subjects (clinical) to define the breadth of viral genes expressed. The viral transcriptome derived from experimental infection was highly correlated with that from clinical infection, validating our experimental latency model. These transcriptomes revealed a broader profile of gene expression during infection in hematopoietic cells than previously appreciated. Further, using recombinant viruses that establish a non-reactivating, latent-like or replicative infection in CD34+ hematopoietic progenitors (HPCs), we defined classes of low to moderately expressed genes that are differentially regulated in latent vs. replicative states of infection. Most of these genes have yet to be studied in depth. By contrast, genes that were highly expressed, were expressed similarly in both latent and replicative infection. From these findings, a model emerges whereby low or moderately expressed genes may have the greatest impact on regulating the switch between viral latency and replication. The core set of viral genes expressed in natural infection and differentially regulated depending on the pattern of infection provides novel insight into the HCMV transcriptome associated with latency in the host and a resource for investigating new virus-host interactions underlying persistence. Significance: Herpesviruses have an extraordinarily complex relationship with their host, persisting for the lifetime of the host by way of a latent infection. Reactivation of replication is associated with significant disease risk, particularly in immunocompromised individuals. We characterize in depth transcriptional profiles of HCMV latency. We show that a broad and concordant viral transcriptome is found in both an experimental model of latency and in asymptomatically infected individuals. We further define genes that are differentially regulated during latent and replicative states- candidates for key regulators controlling the switch between latency and reactivation. This work will help understand the persistence of complex DNA viruses and provides a path towards developing antiviral strategies to control herpesvirus entry into and exit from latency.
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Project description:Primary infection with human cytomegalovirus (HCMV) results in a lifelong infection due to its ability to establish latent infection, with one characterized viral reservoir being hematopoietic cells. Although reactivation from latency causes serious disease in immunocompromised individuals, our molecular understanding of latency is limited. Here, we delineate viral gene expression during natural HCMV persistent infection by analyzing the massive transcriptome sequencing (RNA-seq) atlas generated by the Genotype-Tissue Expression (GTEx) project. This systematic analysis reveals that HCMV persistence in vivo is prevalent in diverse tissues. Notably, we find only viral transcripts that resemble gene expression during various stages of lytic infection with no evidence of any highly restricted latency-associated viral gene expression program. To further define the transcriptional landscape during HCMV latent infection, we also used single-cell RNA-seq and a tractable experimental latency model. In contrast to some current views on latency, we also find no evidence for any highly restricted latency-associated viral gene expression program. Instead, we reveal that latency-associated gene expression largely mirrors a late lytic viral program, albeit at much lower levels of expression. Overall, our work has the potential to revolutionize our understanding of HCMV persistence and suggests that latency is governed mainly by quantitative changes, with a limited number of qualitative changes, in viral gene expression.
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Project description:We introduce target sites for the microRNA (miRNA) miR-142 into the 3’-untranslated region of the human cytomegalovirus (HCMV) IE2 to study the transcriptional effect of IE2 knock-down on both viral and host genes in cells that express miR-142. When comparing transcriptional data from miR-142 expressing macrophages infected with HCMV to macrophages infected with IE2-miR-142 targeted HCMV, we see a knock-down of IE2 and differential regulation of predicted viral targets of IE2 including IE1, vIL-10 and US29. We then generated fibroblasts expressing miR-142 to study the knock-down of IE2 in a different cellular system and find drastic differences in loss of IE2 on the host transcriptional profile in the two different cell types.
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Project description:Human Cytomegalovirus (hCMV) infects a broad range of the population and establishes life-long latency in the infected individuals. Periodically the latently infected virus can reactivate and becomes a significant cause of morbidity and mortality in immunocompromised individuals. Upon reactivation, the repressive chromatin is remodeled to an active form, allowing viral lytic gene transcription, initiated by the expression of viral Immediate Early (IE) genes. During this process, a number of histone modification enzymes, including histone demethylases (HDMs), play important roles in driving IE expression, but the mechanisms involved are not fully understood. To get a better understanding of these mechanisms, we profiled this well-established CMV experimental latency-reactivation model based on TPA (12-O-Tetradecanoylphorbol-13-acetate) induced THP-1 differentiation, which recapitulates many key features of CMV latency and reactivation in vivo, including the important role of viral chromatin in controlling viral IE gene expression.
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Project description:Citrullination is the conversion of arginine-to-citrulline by protein arginine deiminases (PADs), whose dysregulation is implicated in the pathogenesis of various types of cancers and autoimmune diseases. Consistent with the ability of human cytomegalovirus (HCMV) to induce post-translational modifications of cellular proteins to gain a survival advantage, we show that HCMV infection of primary human fibroblasts triggers PAD-mediated citrullination of several host proteins, and that this activity promotes viral fitness. Citrullinome analysis reveals significant changes in deimination levels of both cellular and viral proteins, with interferon (IFN)-inducible protein IFIT1 being the most heavily deiminated one. As genetic depletion of IFIT1 strongly enhances HCMV growth, and in vitro IFIT1 citrullination impairs its ability to bind to 5’-pppRNA, we propose that viral-induced IFIT1 citrullination is a novel mechanism of HCMV evasion from host antiviral resistance. Overall, our findings point to a crucial role of citrullination in subverting cellular responses to viral infection.
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