Identification of herpes simplex virus 1 and host targets of miR-138 by combined RNAseq/PARCLIP
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ABSTRACT:
ORGANISM(S): Mus musculus Human alphaherpesvirus 1 Homo sapiens
PROVIDER: GSE127504 | GEO | 2020/04/27
REPOSITORIES: GEO
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Project description:Identification of herpes simplex virus 1 and host targets of miR-138 by combined RNAseq/PARCLIP
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Project description:MicroRNA miR-138, which is highly expressed in neurons, represses herpes simplex virus 1 (HSV-1) lytic cycle genes by targeting viral ICP0 messenger RNA, thereby promoting viral latency in mice. We found that overexpressed miR-138 also represses lytic processes independently of ICP0 in murine and human neuronal cells; therefore, we investigated whether miR-138 has targets besides ICP0. Using genome-wide RNA sequencing/photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation followed by short interfering RNA knockdown of candidate targets, we identified the host Oct-1 and Foxc1 messenger mRNAs as miR-138's targets, whose gene products are transcription factors important for HSV-1 replication in neuronal cells. OCT-1 has a known role in the initiation of HSV transcription. Overexpression of FOXC1, which was not known to affect HSV-1, promoted HSV-1 replication in murine neurons and ganglia. CRISPR-Cas9 knockout of FOXC1 reduced viral replication, lytic gene expression and miR-138 repression in murine neuronal cells. FOXC1 also collaborated with ICP0 to decrease heterochromatin on viral genes and compensated for the defect of an ICP0-null virus. In summary, miR-138 targets ICP0, Oct-1 and Foxc1 to repress HSV-1 lytic cycle genes and promote epigenetic gene silencing, which together enable favourable conditions for latent infection.
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Project description:Like herpes simplex virus 1 (HSV-1) ICP0 mRNA, HSV-2 ICP0 mRNA is predicted to be targeted by a host neuron-specific microRNA, miR-138. This study was designed to confirm the interaction between HSV-2 ICP0 mRNA and miR-138, and to identify other potential viral and host targets of miR-138 during HSV-2 infection. We performed PAR-CLIP on HSV-2 infected 293T cells overexpressing miR-138 in comparisin to control 293T cells. The results confirmed ICP0 as miR-138's targets, and also identified some other potential viral and host targets of miR-138.
2021-11-01 | GSE155402 | GEO
Project description:This is a part of the study that shows that a host microRNA, miR-138, represses herpes simplex virus 1 (HSV-1) gene expression through both viral and host targets. These PAR-CLIP analyses identified viral and host targets of miR-138 in Neuro-2a (mouse neuroblastoma) and 293T (human embryonic kidney) cells. We constructed two cell lines derived from Neuro-2a cells, one overexpressing miR-138 (N2A138) and one antagonizing miR-138 (N2Aanti138). We also constructed two cell lines derived from 293T cells, one overexpressing miR-138 (293T138) and one control cells (293Tcontrol). Uninfected N2A138 and N2Aanti138 were compared by PAR-CLIP for host targets in Neuro-2A cells. 293T138 and 293Tcontrol cells infected for 4 and 8 hours were compared by PAR-CLIP for HSV-1 targets in 293T cells. 293T138 and 293Tcontrol cells infected for 4 hours were also compared for host targets in 293T cells.
2020-04-27 | GSE127503 | GEO
Project description:Mitochondria have crucial roles in the life and death of mammalian cells, and help to orchestrate host antiviral defences. Here, we show that the ubiquitous human pathogen herpes simplex virus (HSV) induces rapid and complete degradation of host mitochondrial DNA during productive infection of cultured mammalian cells. The depletion of mitochondrial DNA requires the viral UL12 gene, which encodes a conserved nuclease with orthologues in all herpesviruses. We show that an amino-terminally truncated UL12 isoform-UL12.5-localizes to mitochondria and triggers mitochondrial DNA depletion in the absence of other HSV gene products. By contrast, full-length UL12, a nuclear protein, has little or no effect on mitochondrial DNA levels. Our data document that HSV inflicts massive genetic damage to a crucial host organelle and show a novel mechanism of virus-induced shutoff of host functions, which is likely to contribute to the cell death and tissue damage caused by this widespread human pathogen.
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Project description:After infecting peripheral sites, herpes simplex virus (HSV) invades the nervous system and initiates latent infection in sensory neurons. Establishment and maintenance of HSV latency require host survival, and entail repression of productive cycle ("lytic") viral gene expression. We find that a neuron-specific microRNA, miR-138, represses expression of ICP0, a viral transactivator of lytic gene expression. A mutant HSV-1 (M138) with disrupted miR-138 target sites in ICP0 mRNA exhibits enhanced expression of ICP0 and other lytic proteins in infected neuronal cells in culture. Following corneal inoculation, M138-infected mice have higher levels of ICP0 and lytic transcripts in trigeminal ganglia during establishment of latency, and exhibit increased mortality and encephalitis symptoms. After full establishment of latency, the fraction of trigeminal ganglia harboring detectable lytic transcripts is greater in M138-infected mice. Thus, miR-138 is a neuronal factor that represses HSV-1 lytic gene expression, promoting host survival and viral latency.
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Project description:We previously showed that miR-138 can repress herpes simplex virus 1 (HSV-1) ICP0 expression by binding to ICP0 mRNA. However, in this study we found that miR-138 can also repress viral gene expression independent of ICP0. Therefore we conducted this RNAseq experiment to assess the effects of miR-138 on expression of each individual viral gene to search for other viral targets of miR-138
2020-04-27 | GSE127501 | GEO
Project description:Herpes simplex virus mutants lacking the vhs gene are severely attenuated in animal models of pathogenesis and exhibit reduced growth in primary cell culture. As a result of these properties vhs-deleted virus have been proposed as live-attenuated viruses. Despite these findings and their implications for vacccines, the mechanisms by which vhs promotes infection in cell culture and in vivo are not understood. In this study we demonstrate that vhs-deficent viruses replicate to reduced levels in interferon(IFN)- primed cells. Furthermore, vhs-defective viruses induce increased levels of IFN? and IFN?-stimulated genes, and increased levels of eIF2? phosphorylation in infected cells. In addition, we demonstrate a generalized over-expression of viral RNAs following infection with a vhs-deficient virus. This suggests increased expression of IFN pathway inducing double stranded RNA, a potent pathogen-associated molecular pattern (PAMP). Together these data show that vhs likely functions to reduce innate immune responses and thereby acts as critical determinant of viral pathogenesis. Keywords: time course, genetic modification Time course (1,3,6,9 & 12h) of HSV infected mouse embryo fibroblasts. Wild type (KOS) virus is co-hybridized with vhs null virus (NHB). Each time-point is hybridized in quadruplicate.
2008-04-03 | E-GEOD-10962 | biostudies-arrayexpress
Project description:Herpes simplex virus (HSV), a common latent virus in humans, causes certain severe diseases. Extensive use of acyclovir (ACV) results in the development of drug-resistant HSV strains, hence, there is an urgent need to develop new drugs to treat HSV infection. Houttuynia cordata (H. cordata), a natural herbal medicine, has been reported to exhibit anti-HSV effects which is partly NF-κB-dependent. However, the molecular mechanisms by which H. cordata inhibits HSV infection are not elucidated thoroughly. Here, we report that H. cordata water extracts (HCWEs) inhibit the infection of HSV-1, HSV-2, and acyclovir-resistant HSV-1 mainly via blocking viral binding and penetration in the beginning of infection. HCWEs also suppress HSV replication. Furthermore, HCWEs attenuate the first-wave of NF-κB activation, which is essential for viral gene expressions. Further analysis of six compounds in HCWEs revealed that quercetin and isoquercitrin inhibit NF-κB activation and additionally, quercetin also has an inhibitory effect on viral entry. These results indicate that HCWEs can inhibit HSV infection through multiple mechanisms and could be a potential lead for development of new drugs for treating HSV.
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Project description:The Latency-Associated Transcript Locus of Herpes Simplex Virus 1 is a Virulence Determinant in Human Skin
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