scholarly journals TheHerpesviridaeConserved Multifunctional Infected-Cell Protein 27 (ICP27) Is Important but Not Required for Replication and Oncogenicity of Marek’s Disease Alphaherpesvirus

2018 ◽  
Vol 93 (4) ◽  
Author(s):  
Nagendraprabhu Ponnuraj ◽  
Yung-Tien Tien ◽  
Widaliz Vega-Rodriguez ◽  
Andrea Krieter ◽  
Keith W. Jarosinski
Keyword(s):  
Cell Culture ◽  
Infected Cell ◽  
Regulatory Protein ◽  
Natural Host ◽  
Marek's Disease ◽  
Cell Protein ◽  
Marek’S Disease ◽  
Disease Induction ◽  
Infected Cell Protein ◽  
Infected Cell Protein 27

ABSTRACTTheHerpesviridaeconserved infected-cell protein 27 (ICP27) is essential for cell culture-based replication of most herpesviruses studied. For members of theAlphaherpesvirinae, ICP27 regulates the expression of many viral genes, including expression of pUL44 (gC), pUL47 (VP13/14), and pUL48 (VP16). These three viral proteins are dysregulated during Marek’s disease alphaherpesvirus (MDV) replication in cell culture. MDV replicates in a highly cell-associated manner in cell culture, producing little to no infectious virus. In contrast, infectious cell-free MDV is produced in specialized feather follicle epithelial (FFE) cells of infected chickens, in which these three genes are abundantly expressed. This led us to hypothesize that MDV ICP27, encoded by gene UL54, is a defining factor for the dysregulation of gC, pUL47, and pUL48 and, ultimately, ineffective virus production in cell culture. To address ICP27’s role in MDV replication, we generated recombinant MDV with ICP27 deleted (vΔ54). Interestingly, vΔ54 replicated, but plaque sizes were significantly reduced compared to those of parental viruses. The reduced cell-to-cell spread was due to ICP27 since plaque sizes were restored in rescued viruses, as well as when vΔ54 was propagated in cells expressing ICP27 intrans. In chickens, vΔ54 replicated, induced disease, and was oncogenic but was unable to transmit from chicken to chicken. To our knowledge, this is the first report showing that theHerpesviridaeconserved ICP27 protein is dispensable for replication and disease induction in its natural host.IMPORTANCEMarek’s disease (MD) is a devastating oncogenic disease that affects the poultry industry and is caused by MD alphaherpesvirus (MDV). Current vaccines block induction of disease but do not block chicken-to-chicken transmission. There is a knowledge gap in our understanding of how MDV spreads from chicken to chicken. We studied theHerpesviridaeconserved ICP27 regulatory protein in cell culture and during MDV infection in chickens. We determined that MDV ICP27 is important but not required for replication in both cell culture and chickens. In addition, MDV ICP27 was not required for disease induction or oncogenicity but was required for chicken-to-chicken transmission. This study is important because it addresses the role of ICP27 during infection in the natural host and provides important information for the development of therapies to protect chickens against MD.

scholarly journals Expression of the Conserved Herpesvirus Protein Kinase (CHPK) of Marek’s Disease Alphaherpesvirus in the Skin Reveals a Mechanistic Importance for CHPK during Interindividual Spread in Chickens

2019 ◽  
Vol 94 (5) ◽  
Author(s):  
Andrea Krieter ◽  
Nagendraprabhu Ponnuraj ◽  
Keith W. Jarosinski
Keyword(s):  
Cell Culture ◽  
Protein Kinase ◽  
Critical Role ◽  
Tumor Formation ◽  
Natural Host ◽  
Marek's Disease ◽  
Marek’S Disease ◽  
Aberrant Expression ◽  
Content Type ◽  
Conserved Genes

ABSTRACT The Herpesviridae encode many conserved genes, including the conserved herpesvirus protein kinase (CHPK) that has multifunctional properties. In most cases, herpesviruses lacking CHPK can propagate in cell culture to various degrees, depending on the virus and cell culture system. However, in the natural animal model system of Marek’s disease alphaherpesvirus (MDV) in chickens, CHPK is absolutely required for interindividual spread from chicken to chicken. The lack of biological reagents for chicken and MDV has limited our understanding of this important gene during interindividual spread. Here, we engineered epitope-tagged proteins in the context of virus infection in order to detect CHPK in the host. Using immunofluorescence assays and Western blotting during infection in cell culture and in chickens, we determined that the invariant lysine 170 (K170) of MDV CHPK is required for interindividual spread and autophosphorylation of CHPK and that mutation to methionine (M170) results in instability of the CHPK protein. Using these newly generated viruses allowed us to examine the expression of CHPK in infected chickens, and these results showed that mutant CHPK localization and late viral protein expression were severely affected in feather follicles wherein MDV is shed, providing important information on the requirement of CHPK for interindividual spread. IMPORTANCE Marek’s disease in chickens is caused by Gallid alphaherpesvirus 2, better known as Marek’s disease alphaherpesvirus (MDV). Current vaccines only reduce tumor formation but do not block interindividual spread from chicken to chicken. Understanding MDV interindividual spread provides important information for the development of potential therapies to protect against Marek’s disease while also providing a reliable natural host in order to study herpesvirus replication and pathogenesis in animals. Here, we studied the conserved Herpesviridae protein kinase (CHPK) in cell culture and during infection in chickens. We determined that MDV CHPK is not required for cell-to-cell spread, for disease induction, and for oncogenicity. However, it is required for interindividual spread, and mutation of the invariant lysine (K170) results in stability issues and aberrant expression in chickens. This study is important because it addresses the critical role CHPK orthologs play in the natural host.

scholarly journals The Glucocorticoid Receptor (GR) Stimulates Herpes Simplex Virus 1 Productive Infection, in Part Because the Infected Cell Protein 0 (ICP0) Promoter Is Cooperatively Transactivated by the GR and Krüppel-Like Transcription Factor 15

2019 ◽  
Vol 93 (6) ◽  
Author(s):  
Jeffery B. Ostler ◽  
Kelly S. Harrison ◽  
Kayla Schroeder ◽  
Prasanth Thunuguntla ◽  
Clinton Jones
Keyword(s):  
Transcription Factor ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Infected Cell ◽  
Promoter Activity ◽  
Productive Infection ◽  
Cell Protein ◽  
Herpes Simplex Virus 1 ◽  
Infected Cell Protein ◽  
Infected Cell Protein 0

ABSTRACTFollowing acute infection, herpes simplex virus 1 (HSV-1) establishes lifelong latency in neurons. Physical, emotional, and chemical stresses are linked to increasing the incidence of reactivation from latency, but the mechanism of action is not well understood. In general, stress increases corticosteroid levels, leading to activation of the glucocorticoid receptor (GR), a pioneer transcription factor. Consequently, we hypothesized that stress-mediated activation of the GR can stimulate productive infection and viral gene expression. New studies demonstrated that the GR-specific antagonist (CORT-108297) significantly reduced HSV-1 productive infection in mouse neuroblastoma cells (Neuro-2A). Additional studies demonstrated that the activated GR and Krüppel-like transcription factor 15 (KLF15) cooperatively transactivated the infected cell protein 0 (ICP0) promoter, a crucial viral regulatory protein. Interestingly, the synthetic corticosteroid dexamethasone and GR or KLF15 alone had little effect on ICP0 promoter activity in transfected Neuro-2A or Vero cells. Chromatin immunoprecipitation (ChIP) studies revealed that the GR and KLF15 occupied ICP0 promoter sequences important for transactivation at 2 and 4 h after infection; however, binding was not readily detected at 6 h after infection. Similar results were obtained for cells transfected with the full-length ICP0 promoter. ICP0 promoter sequences lack a consensus “whole” GR response element (GRE) but contain putative half-GREs that were important for dexamethasone induced promoter activity. The activated GR stimulates expression of, and interacts with, KLF15; consequently, these data suggest KLF15 and the GR form a feed-forward loop that activates viral gene expression and productive infection following stressful stimuli.IMPORTANCEThe ability of herpes simplex virus 1 (HSV-1) to periodically reactivate from latency results in virus transmission and recurrent disease. The incidence of reactivation from latency is increased by chronic or acute stress. Stress increases the levels of corticosteroids, which bind and activate the glucocorticoid receptor (GR). Since GR activation is an immediate early response to stress, we tested whether the GR influences productive infection and the promoter that drives infected cell protein 0 (ICP0) expression. Pretreatment of cells with a GR-specific antagonist (CORT-108297) significantly reduced virus replication. Although the GR had little effect on ICP0 promoter activity alone, the Krüppel-like transcription factor 15 (KLF15) cooperated with the GR to stimulate promoter activity in transfected cells. In transfected or infected cells, the GR and KLF15 occupied ICP0 sequences important for transactivation. Collectively, these studies provide insight into how stress can directly stimulate productive infection and viral gene expression.

Studies on the Etiology of Marek's Disease. II. Finding of a Herpesvirus in Cell Culture

1968 ◽  
Vol 127 (1) ◽  
pp. 177-182 ◽  
Author(s):  
K. Nazerian ◽  
J. J. Solomon ◽  
R. L. Witter ◽  
B. R. Burmester
Keyword(s):  
Cell Culture ◽  
Marek's Disease ◽  
Marek’S Disease

scholarly journals ICP22/IE63 Mediated Transcriptional Regulation and Immune Evasion: Two Important Survival Strategies for Alphaherpesviruses

2021 ◽  
Vol 12 ◽  
Author(s):  
Qing He ◽  
Ying Wu ◽  
Mingshu Wang ◽  
Shun Chen ◽  
Renyong Jia ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Immune Evasion ◽  
Viral Infections ◽  
Immune Escape ◽  
Regulatory Protein ◽  
Survival Strategies ◽  
Cell Protein ◽  
Host Immune System ◽  
Early Protein ◽  
Infected Cell Protein

In the process of infecting the host, alphaherpesviruses have derived a series of adaptation and survival strategies, such as latent infection, autophagy and immune evasion, to survive in the host environment. Infected cell protein 22 (ICP22) or its homologue immediate early protein 63 (IE63) is a posttranslationally modified multifunctional viral regulatory protein encoded by all alphaherpesviruses. In addition to playing an important role in the efficient use of host cell RNA polymerase II, it also plays an important role in the defense process of the virus overcoming the host immune system. These two effects of ICP22/IE63 are important survival strategies for alphaherpesviruses. In this review, we summarize the complex mechanism by which the ICP22 protein regulates the transcription of alphaherpesviruses and their host genes and the mechanism by which ICP22/IE63 participates in immune escape. Reviewing these mechanisms will also help us understand the pathogenesis of alphaherpesvirus infections and provide new strategies to combat these viral infections.

scholarly journals The Herpes Simplex Virus-1 Transactivator Infected Cell Protein-4 Drives VEGF-A Dependent Neovascularization

2011 ◽  
Vol 7 (10) ◽  
pp. e1002278 ◽  
Author(s):  
Todd Wuest ◽  
Min Zheng ◽  
Stacey Efstathiou ◽  
William P. Halford ◽  
Daniel J. J. Carr
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Infected Cell ◽  
Cell Protein ◽  
Herpes Simplex Virus 1 ◽  
Infected Cell Protein ◽  
Simplex Virus

scholarly journals The herpes simplex virus type 1 infected cell protein 22

2010 ◽  
Vol 25 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Fu-sen Lin ◽  
Qiong Ding ◽  
Hong Guo ◽  
Alan C. Zheng
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Infected Cell ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Cell Protein ◽  
Infected Cell Protein ◽  
Simplex Virus
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