Lytic HSV-1 infection induces the multifunctional transcription factor Early Growth Response-1 (EGR-1) in rabbit corneal cells

Bedadala, Gautam R; Palem, Jayavardhana R; Graham, Lorna; Hill, James M.; McFerrin, Harris E.; Hsia, Victor

doi:10.1186/1743-422x-8-262

Cited by 21 publications

(31 citation statements)

References 55 publications

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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%

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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%

“…Its expression is found to be correlated to infection by several viruses[2]. These evidences suggest that Egr-1 may play a role in viral gene expression and replication.…”

Section: Introductionmentioning

confidence: 99%

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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“…The protocol was described previously (19, 47). In short, cell extract was subjected to gel electrophoresis and transferred by iBlot® Gel Transfer Device (Life Technology, Cat#: IB1001).…”

Section: Methodsmentioning

confidence: 99%

Thyroid hormone-dependent epigenetic suppression of herpes simplex virus-1 gene expression and viral replication in differentiated neuroendocrine cells

Figliozzi

Chen

Balish

et al. 2014

Journal of the Neurological Sciences

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A global HSV-1 gene repression occurs during latency in sensory neurons where most viral gene transcriptions are suppressed. The molecular mechanisms of gene silencing and how stress factors trigger the reactivation are not well understood. Thyroid hormones are known to be altered due to stress, and with its nuclear receptor impart transcriptional repression or activation depending upon the hormone level. Therefore we hypothesized that triiodothyronine (T3) treatment of infected differentiated neuron like cells would reduce the ability of HSV-1 to produce viral progeny compared to untreated infected cells. Previously we identified putative thyroid hormone receptor elements (TREs) within the promoter regions of HSV-1 thymidine kinase (TK) and other key genes. Searching for a human cell line that can model neuronal HSV-1 infection, we performed HSV-1 infection experiments on differentiated human neuroendocrine cells, LNCaP. Upon androgen deprivation these cells undergo complete differentiation and exhibit neuronal-like morphology and physiology. These cells were readily infected by our HSV-1 recombinant virus, expressing GFP and maintaining many processes iconic of dendritic morphology. Our results demonstrated that differentiated LNCaP cells produced suppressive effects on HSV-1 gene expression and replication compared to its undifferentiated counterpart and T3 treatment have further decreased the viral plaque counts compared to untreated cells. Upon washout of the T3 viral plaque counts were restored, indicating an increase of viral replication. The qRT-PCR experiments using primers for TK showed reduced expression under T3 treatment. ChIP assays using a panel of antibodies for H3 lysine 9 epigenetic marks showed increased repressive marks on the promoter regions of TK. In conclusion we have demonstrated a T3 mediated quiescent infection in differentiated LNCaP cells that has potential to mimic latent infection. In this HSV-1 infection model thyroid hormone treatment caused decreased viral replication, repressed TK expression and increased repressive histone tail marks on the TK promoter.

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“…Interestingly, a previous report showed that HSV-1 infection activates the ERK/mitogen-activated protein kinase (MAPK) signaling pathway (39). Moreover, it has been shown that HSV-1 lytic infection induces Egr1 in rabbit corneal cells (40). Oxidative stress is capable of initiating the DDR (41) and is reported to enhance the expression of Egr1 (42), and HSV-1 has the ability to induce neuronal oxidative stress (43).…”

mentioning

confidence: 99%

Herpes Simplex Virus 1 Upregulates p35, Alters CDK-5 Localization, and Stimulates CDK-5 Kinase Activity during Acute Infection in Neurons

Mostafa

Sels

Davido

2015

J Virol

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The cyclin-dependent kinase 5 (CDK-5) activating protein, p35, is important for acute herpes simplex virus 1 (HSV-1) replication in mice. This report shows that HSV-1 increases p35 levels, changes the primary localization of CDK-5 from the nucleus to the cytoplasm, and enhances CDK-5 activity during lytic or acute infection. Infected neurons also stained positive for the DNA damage response (DDR) marker ␥H2AX. We propose that CDK-5 is activated by the DDR to protect infected neurons from apoptosis. Herpes simplex virus 1 (HSV-1) is a human pathogen that establishes lifelong latent infection in sensory neurons (1, 46). It is not well understood how the virus switches from lytic to latent infections in neurons and the mechanisms involved in reversing this switch under stress stimuli to initiate reactivation. It is vital that the neurons survive an infection by HSV-1 if the virus is to efficiently establish a latent infection or reactivate. Not surprisingly, HSV-1 has developed countermeasures to prevent neuronal apoptosis, in part, with the expression of the latency-associated transcripts (LATs) (2-4). While the contribution of viral gene products that possess antiapoptotic activities has been a major area of interest in HSV-1 research, the role of cellular factors involved in neuronal survival has received limited attention.One neuronal factor that is highly active in postmitotic neurons and is required for neuronal survival during stress is cyclindependent kinase 5 (CDK-5) (5, 6). CDK-5 regulates many neuronal processes (reviewed in reference 7) and has been shown to play important roles in both neuronal survival and death. Inactivation of CDK-5 has been shown to trigger neuronal death (8-11). On the other hand, a survival function for CDK-5 is evident when neurons are stressed (12-16). For its activation, CDK-5 binds to p35 or a related protein, p39, which also modulate CDK-5's subcellular localization (17)(18)(19)(20). Notably the activity of CDK-5 directly correlates with the levels of its major activator, p35, and both are expressed predominantly in neurons (21), which likely explains why CDK-5 is mainly active in neurons, although it is constitutively expressed in many cell types (17,22).We have previously shown that HSV-1 acute replication is impaired in the eyes and trigeminal ganglia (TG) of p35 knockout mice, reducing the establishment of latency and reactivation (23). Given this previous result, we sought to determine whether HSV-1 altered the expression or subcellular localization of the p35 and CDK-5 proteins during acute infection.HSV-1 infection induces p35 protein levels. To examine how HSV-1 acute TG infection affects p35, wild-type HSV (KOS)-infected TG were harvested 3 days postinfection, as previously described (24,25). TG sections were immunostained for both the HSV-1 immediate early protein, ICP0, used as a marker for productively infected neurons, and p35. As shown in Fig. 1A, HSV-1-infected neurons showed an increase in p35 staining compared to mock-infected cells, with a distribution that...

show abstract

Lytic HSV-1 infection induces the multifunctional transcription factor Early Growth Response-1 (EGR-1) in rabbit corneal cells

Cited by 21 publications

References 55 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

Thyroid hormone-dependent epigenetic suppression of herpes simplex virus-1 gene expression and viral replication in differentiated neuroendocrine cells

Herpes Simplex Virus 1 Upregulates p35, Alters CDK-5 Localization, and Stimulates CDK-5 Kinase Activity during Acute Infection in Neurons

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