Marek's Disease Virus Disables the ATR-Chk1 Pathway by Activating STAT3

ABSTRACT Oncogenic virus replication often leads to genomic instability, causing DNA damage and inducing the DNA damage response (DDR) pathway. The DDR pathway is a cellular pathway that senses DNA damage and regulates the cell cycle to maintain genomic stability. Therefore, the DDR pathway is critical for the viral lifecycle and tumorigenesis. Marek’s disease virus (MDV), an alphaherpesvirus that causes lymphoma in chickens, has been shown to induce DNA damage in infected cells. However, the interaction between MDV and the host DDR is unclear. In this study, we observed that MDV infection causes DNA strand breakage in chicken fibroblast (CEF) cells along with an increase in the DNA damage markers p53 and p21. Interestingly, we showed that phosphorylation of STAT3 was increased during MDV infection, concomitantly with a decrease of Chk1 phosphorylation. In addition, we found that MDV infection was enhanced by VE-821, an ATR-specific inhibitor, but attenuated by hydroxyurea, an ATR activator. Moreover, inhibition of STAT3 phosphorylation by Stattic eliminates the ability of MDV to inhibit Chk1 phosphorylation. Finally, we showed that MDV replication was decreased by Stattic treatment. Taken together, these results suggest that MDV disables the ATR-Chk1 pathway through STAT3 activation to benefit its replication. IMPORTANCE MDV is used as a biomedical model to study virus-induced lymphoma due to the similar genomic structures and physiological characteristics of MDV and human herpesviruses. Upon infection, MDV induces DNA damage, which may activate the DDR pathway. The DDR pathway has a dual impact on viruses because it manipulates repair and recombination factors to facilitate viral replication and also initiates antiviral action by regulating other signaling pathways. Many DNA viruses evolve to manipulate the DDR pathway to promote virus replication. In this study, we identified a mechanism used by MDV to inhibit ATR-Chk1 pathways. ATR is a cellular kinase that responds to broken single-stranded DNA, which has been less studied in MDV infection. Our results suggest that MDV infection activates STAT3 to disable the ATR-Chk1 pathway, which is conducive to viral replication. This finding provides new insight into the role of STAT3 in interrupting the ATR-Chk1 pathway during MDV replication.

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Marek’s disease virus (MDV) ubiquitin-specific protease (USP) performs critical functions beyond its enzymatic activity during virus replication

Virology ◽

10.1016/j.virol.2013.01.003 ◽

2013 ◽

Vol 437 (2) ◽

pp. 110-117 ◽

Cited By ~ 6

Author(s):

Inês B. Veiga ◽

Keith W. Jarosinski ◽

Benedikt B. Kaufer ◽

Nikolaus Osterrieder

Keyword(s):

Enzymatic Activity ◽

Disease Virus ◽

Virus Replication ◽

Marek's Disease Virus ◽

Marek's Disease ◽

Marek’S Disease Virus ◽

Marek’S Disease ◽

Specific Protease ◽

Ubiquitin Specific Protease

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Relationship between tumour development and detection of Marek’s disease virus in the feather follicular epithelium of older chickens

Acta Veterinaria Hungarica ◽

10.1556/avet.2012.028 ◽

2012 ◽

Vol 60 (3) ◽

pp. 333-342

Author(s):

Mitsutaka Ikezawa ◽

Jun Sasaki ◽

Masanobu Goryo

Keyword(s):

Disease Virus ◽

Virus Replication ◽

Marek's Disease Virus ◽

Lymphoid Cells ◽

Marek's Disease ◽

Marek’S Disease Virus ◽

Marek’S Disease ◽

Tumour Development ◽

Group A ◽

The Relationship

To demonstrate the relationship between tumour development and virus replication, eight specific-pathogen-free pullets of line P2 (Group P; 14 weeks old) and five adult chickens (Group A; 96 weeks old) were inoculated with virulent Marek’s disease virus (vMDV). Five chickens of Group P died or were euthanised due to moribund condition following the development of neoplastic lesions between days 53 and 91. On histopathological examination, these lesions were characterised by the proliferation of lymphoid cells of variable size. On analysis by polymerase chain reaction (PCR), the MDVmeqgene was detected in Group P from day 21, and it was continuously identified in five chickens until they died or were euthanised. Abnormal signs and histopathological changes were not observed in chickens of Group A. The MDVmeqgene was temporarily detected in some chickens of Group A, but it remained almost undetectable throughout the experimental period. In older chickens inoculated with vMDV, the onset of MD lymphoma development tended to be delayed as compared with the young chicks. The relationship between MD lymphoma development and virus replication in older chickens has been suggested. Our data might indicate the underlying existence of an age-related resistance to vMDV challenge.

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Marek's disease virus influences the core gut microbiome of the chicken during the early and late phases of viral replication

FEMS Microbiology Ecology ◽

10.1111/1574-6941.12392 ◽

2014 ◽

Vol 90 (1) ◽

pp. 300-312 ◽

Cited By ~ 18

Author(s):

Sudeep Perumbakkam ◽

Henry D. Hunt ◽

Hans H. Cheng

Keyword(s):

Viral Replication ◽

Disease Virus ◽

Gut Microbiome ◽

Marek's Disease Virus ◽

Marek's Disease ◽

Marek’S Disease Virus ◽

Marek’S Disease ◽

The Core

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Marek’s disease virus US3 protein kinase phosphorylates chicken HDAC 1 and 2 and regulates viral replication and pathogenesis

PLoS Pathogens ◽

10.1371/journal.ppat.1009307 ◽

2021 ◽

Vol 17 (2) ◽

pp. e1009307

Author(s):

Yifei Liao ◽

Blanca Lupiani ◽

Mohammad AI-Mahmood ◽

Sanjay M. Reddy

Keyword(s):

Protein Kinase ◽

Disease Virus ◽

Specific Inhibitor ◽

Marek's Disease Virus ◽

Marek's Disease ◽

Marek’S Disease Virus ◽

Marek’S Disease ◽

Virus Growth ◽

Histone Deacetylase 1

Marek’s disease virus (MDV) is a potent oncogenic alphaherpesvirus that elicits a rapid onset of malignant T-cell lymphomas in chickens. Three MDV types, including GaHV-2 (MDV-1), GaHV-3 (MDV-2) and MeHV-1 (HVT), have been identified and all encode a US3 protein kinase. MDV-1 US3 is important for efficient virus growth in vitro. To study the role of US3 in MDV replication and pathogenicity, we generated MDV-1 US3-null virus and chimeric viruses by replacing MDV-1 US3 with MDV-2 or HVT US3. Using MD as a natural virus-host model, we showed that both MDV-2 and HVT US3 partially rescued the growth deficiency of MDV-1 US3-null virus. In addition, deletion of MDV-1 US3 attenuated the virus resulting in higher survival rate and lower MDV specific tumor incidence, which could be partially compensated by MDV-2 and HVT US3. We also identified chicken histone deacetylase 1 (chHDAC1) as a common US3 substrate for all three MDV types while only US3 of MDV-1 and MDV-2 phosphorylate chHDAC2. We further determined that US3 of MDV-1 and HVT phosphorylate chHDAC1 at serine 406 (S406), while MDV-2 US3 phosphorylates S406, S410, and S415. In addition, MDV-1 US3 phosphorylates chHDAC2 at S407, while MDV-2 US3 targets S407 and S411. Furthermore, biochemical studies show that MDV US3 mediated phosphorylation of chHDAC1 and 2 affect their stability, transcriptional regulation activity, and interaction network. Using a class I HDACs specific inhibitor, we showed that MDV US3 mediated phosphorylation of chHDAC1 and 2 is involved in regulation of virus replication. Overall, we identified novel substrates for MDV US3 and characterized the role of MDV US3 in MDV pathogenesis.

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Marek'S Disease Virus Infection In the Eye: Chronological Study Of the Lesions, Virus Replication, and Vaccine-Induced Protection

Avian Diseases Digest ◽

10.1637/1933-5334-3.4.e2 ◽

2008 ◽

Vol 3 (4) ◽

pp. e2-e5

Author(s):

Arun K. R. Pandiri ◽

Aneg L. Cortes ◽

Lucy F. Lee ◽

I. M. Gimeno

Keyword(s):

Virus Infection ◽

Disease Virus ◽

Virus Replication ◽

Marek's Disease Virus ◽

Marek's Disease ◽

Marek’S Disease Virus ◽

Marek’S Disease

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Inhibition of DNA-Sensing Pathway by Marek's Disease Virus VP23 Protein through Suppression of Interferon Regulatory Factor 7 Activation

Journal of Virology ◽

10.1128/jvi.01934-18 ◽

2018 ◽

Vol 93 (4) ◽

Cited By ~ 8

Author(s):

Li Gao ◽

Kai Li ◽

Yu Zhang ◽

Yongzhen Liu ◽

Changjun Liu ◽

...

Keyword(s):

Viral Replication ◽

Disease Virus ◽

Marek's Disease Virus ◽

Innate Immune ◽

Marek's Disease ◽

Type I ◽

Marek’S Disease Virus ◽

Marek’S Disease ◽

Dna Sensing ◽

Regulatory Factor

ABSTRACTThe type I interferon (IFN) response is the first line of host innate immune defense against viral infection; however, viruses have developed multiple strategies to antagonize host IFN responses for efficient infection and replication. Here, we report that Marek’s disease virus (MDV), an oncogenic herpesvirus, encodes VP23 protein as a novel immune modulator to block the beta interferon (IFN-β) activation induced by cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) in chicken fibroblasts and macrophages. VP23 overexpression markedly reduces viral DNA-triggered IFN-β production and promotes viral replication, while knockdown of VP23 during MDV infection enhances the IFN-β response and suppresses viral replication. VP23 selectively inhibits IFN regulatory factor 7 (IRF7) but not nuclear factor κB (NF-κB) activation. Furthermore, we found that VP23 interacts with IRF7 and blocks its binding to TANK-binding kinase 1 (TBK1), thereby inhibiting IRF7 phosphorylation and nuclear translocation, resulting in reduced IFN-β production. These findings expand our knowledge of DNA sensing in chickens and reveal a mechanism through which MDV antagonizes the host IFN response.IMPORTANCEDespite widespread vaccination, Marek’s disease (MD) continues to pose major challenges for the poultry industry worldwide. MDV causes immunosuppression and deadly lymphomas in chickens, suggesting that this virus has developed a successful immune evasion strategy. However, little is known regarding the initiation and modulation of the host innate immune response during MDV infection. This study demonstrates that the cGAS-STING DNA-sensing pathway is critical for the induction of the IFN-β response against MDV infection in chicken fibroblasts and macrophages. An MDV protein, VP23, was found to efficiently inhibit the cGAS-STING pathway. VP23 selectively inhibits IRF7 but not NF-κB activation. VP23 interacts with IRF7 and blocks its binding to TBK1, thereby suppressing IRF7 activation and resulting in inhibition of the DNA-sensing pathway. These findings expand our knowledge of DNA sensing in chickens and reveal a mechanism through which MDV antagonizes the host IFN response.

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