Suppression of transcription factor early growth response 1 reduces herpes simplex virus lethality in mice

Chen, Shih‐Heng; Yao, Hui-Wen; Chen, I-Te; Shieh, Biehuoy; Li, Ching; Chen, Shun Hua

doi:10.1172/jci35114

Cited by 21 publications

(30 citation statements)

References 37 publications

(48 reference statements)

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“…This observation proposed a connection between neuronal stress and HSV reactivation from latency, suggesting that activation of the Egr-2 from the same stress/stimuli responses may result in LAT suppression and thus play a role in reactivation by abolishing latency. Additional and current studies indicated that during acute infection HSV-1 can directly induce Egr-1 and enhance viral gene expression and replication [2,13,21]. All these results supported the roles of EGR proteins in suppressing latency and promote lytic infection.…”

Section: Discussionsupporting

confidence: 52%

Induction of Transcription Factor Early Growth Response Protein 1 during HSV-1 Infection Promotes Viral Replication in Corneal Cells

Hsia

Graham

Bedadala

et al. 2013

BMRJ

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Aims To understand the mechanisms of Early Growth Response Protein 1 (Egr-1) induction upon HSV-1 lytic infection and its roles in regulating viral gene expression and replication. Study Design Rabbit corneal cell line SIRC and other cell lines were infected by HSV-1 to investigate the Egr-1 induction and its occupancy on the viral genome in different conditions. UV-inactivated HSV-1 and a recombinant virus over-expressing Egr-1 were generated to evaluate the regulatory effects on viral gene expression and replication during the infection. Methodology Egr-1 induction triggered by viral infection was determined by Western Blot analyses and immune-fluorescent microscopy. Real-time RT-PCR and a novel Cignal™ Reporter Assay were used for quantitative measurement of Egr-1 expression. Chromatin Immuno-precipitation (ChIP) was performed to address the Egr-1 occupancy to the viral regulatory sequences and the influence on viral replication was assessed by plaque assays. Results Our results indicated that Egr-1 expression requires viral gene expression since the UV-inactivated HSV-1 failed to produce Egr-1 protein. Blockade of viral replication did not block the Egr-1 protein synthesis, supporting the hypothesis that HSV-1 replication was not essential for Egr-1 production. Chromatin immune-precipitation (ChIP) and RT-PCR assays demonstrated that induced Egr-1 was able to interact with key regulatory elements near HSV-1 immediate-early (IE) genes and promote viral gene expression. Recombinant virus overexpressing Egr-1 revealed that Egr-1 enhanced the viral replication and the release of infectious virus. Conclusion Together these results concluded that HSV-1 triggers the expression of an important host transcription factor Egr-1 via a unique mechanism and benefit the viral gene expression and replication.

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Section: Discussionsupporting

confidence: 52%

Induction of Transcription Factor Early Growth Response Protein 1 during HSV-1 Infection Promotes Viral Replication in Corneal Cells

Hsia

Graham

Bedadala

et al. 2013

BMRJ

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“…We also showed that Egr-1 could activate the promoter of the HSV-1 gene, infected cell protein 4 (ICP4), which has recently been reported to activate the VEGF-A promoter (10,44). The induced FGF-2 and VEGF-A can, in turn, augment Egr-1 expression (27,35).…”

mentioning

confidence: 79%

“…Additionally, HSV-1 infection may increase Egr-1 expression indirectly through cellular factors. We previously revealed that the 5= end of the Egr-1 promoter containing a cyclic AMP (cAMP) response element and binding sites for several transcription factors, including SP1, AP1, and Egr-1 itself, was required for HSV infection to increase Egr-1 expression (1,10). HSV infection increases the expression or the activities of cAMP, SP1, and AP1 (6,18,21) and may enhance Egr-1 expression in infected cells through these mediators.…”

Section: Discussionmentioning

confidence: 99%

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Suppression of Transcription Factor Early Growth Response 1 Reduces Herpes Simplex Virus 1-Induced Corneal Disease in Mice

Yao

Chen

et al. 2012

J Virol

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bHerpes simplex virus 1 replication initiates angiogenesis and inflammation in the cornea. This can result in herpetic stromal keratitis (HSK), which is a leading cause of infection-induced corneal blindness. Host cellular factors mediate the progression of HSK, but little is known about these cellular factors and their mechanisms of action. We show here that the expression of the cellular transcription factor early growth response 1 (Egr-1) in HSV-1-infected mouse corneas was enhanced. Enhanced Egr-1 expression aggravated HSK by increasing viral replication and subsequent neovascularization with high levels of potent angiogenic factors, fibroblast growth factor 2, and vascular endothelial growth factor. Furthermore, Egr-1 deficiency due to a targeted disruption of the gene or knockdown of Egr-1 expression topically using a DNA-based enzyme significantly reduced HSK by decreasing both viral replication and the angiogenic response. The present study provides the first evidence that endogenous Egr-1 aggravates HSK and that blocking Egr-1 reduces corneal damage.

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“…Vero cells were maintained and propagated according to the instructions of the American Type Culture Collection. Wild-type HSV-1 strains 294.1 (15)(16)(17)(18) and McKrae (kindly provided by Donald Coen, Harvard Medical School) were propagated and titrated on Vero cell monolayers. All mouse experiment protocols were approved by the Laboratory Animal Committee of National Cheng Kung University.…”

Section: Methodsmentioning

confidence: 99%

In Vivo Reactivation of Latent Herpes Simplex Virus 1 in Mice Can Occur in the Brain before Occurring in the Trigeminal Ganglion

Yao

Ling

Tung

et al. 2014

J Virol

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Herpes simplex virus 1 (HSV-1) establishes latency in neurons of the brains and sensory ganglia of humans and experimentally infected mice. The latent virus can reactivate to cause recurrent infection. Both primary and recurrent infections can induce diseases, such as encephalitis. In humans, the majority of encephalitis cases occur as a recurrent infection. However, in the past, numerous mouse studies documented that viral reactivation occurs efficiently in the ganglion, but extremely rarely in the brain, when assessed ex vivo by cultivating minced tissue explants. Here, we compare the brains and the trigeminal ganglia of mice latently infected with HSV-1 (strain 294.1 or McKrae) for levels of viral genomes and in vivo reactivation. The numbers of copies of 294.1 and McKrae genomes in the brain stem were significantly greater than those in the trigeminal ganglion. Most importantly, 294.1 and McKrae reactivation was detected in the brain stems earlier than in the trigeminal ganglia of mice treated with hyperthermia to reactivate latent virus in vivo. In addition, the brain stem yielded reactivated virus at a high frequency compared with the trigeminal ganglion, especially in mice latently infected with 294.1 after hyperthermia treatment. These results provide evidence that recurrent brain infection can be induced by the reactivation of latent virus in the brain in situ. IMPORTANCEHerpes simplex virus 1 (HSV-1) establishes latency in neurons of the brains and sensory ganglia of humans and experimentally infected mice. The latent virus can reactivate to cause recurrent infection. In the past, studies of viral reactivation focused on the ganglion, because efficient viral reactivation was detected in the ganglion but not in the brain when assessed ex vivo by cultivating mouse tissue explants. In this study, we report that the brain contains more viral genomes than the trigeminal ganglion in latently infected mice. Notably, the brain yields reactivated virus early and efficiently compared with the trigeminal ganglion after mice are stimulated to reactivate latent virus. Our findings raise the potential importance of HSV-1 latent infection and reactivation in the brain.

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Suppression of transcription factor early growth response 1 reduces herpes simplex virus lethality in mice

Cited by 21 publications

References 37 publications

Induction of Transcription Factor Early Growth Response Protein 1 during HSV-1 Infection Promotes Viral Replication in Corneal Cells

Induction of Transcription Factor Early Growth Response Protein 1 during HSV-1 Infection Promotes Viral Replication in Corneal Cells

Suppression of Transcription Factor Early Growth Response 1 Reduces Herpes Simplex Virus 1-Induced Corneal Disease in Mice

In Vivo Reactivation of Latent Herpes Simplex Virus 1 in Mice Can Occur in the Brain before Occurring in the Trigeminal Ganglion

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