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Viruses
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Marek’s Disease Virus
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Marek’s Disease Virus

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 15735

Special Issue Editors

Prof. Dr. Sanjay Reddy

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Guest Editor
Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station, TX 77943, USA
Interests: viruses; avian virus vectors; poultry viral vaccines; poultry diseases; oncogenesis; pathogenesis; molecular virology; avian herpesviruses
Dr. Yongxiu Yao

E-Mail Website
Guest Editor
The Pirbright Institute, Pirbright GU24 0NE, UK
Interests: molecular virology; viral oncogenesis; viral latency/reactivation; vectored vaccines
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Blanca Lupiani

E-Mail Website
Guest Editor
Department of Veterinary Pathobiology, College of Veterinary Medicine & Biomedical Sciences, Texas A&M University, College Station TX 77943, USA
Interests: herpesvirus vectors; poultry viral vaccines; oncogenesis; pathogenesis; molecular virology; avian oncogenic viruses

Special Issue Information

Dear Colleagues,

Marek’s disease virus (MDV) is a member of alphaherpesviruses associated with Marek’s disease (MD), a highly contagious neoplastic disease in chickens. MD is one of the major diseases affecting poultry health and welfare worldwide with a global annual estimated loss of around USD 2 billion to the poultry industry. MD has been controlled for five decades by the widespread use of live attenuated vaccines. One of the major challenges facing the vaccination strategy is the evolution of viruses towards greater virulence, forcing the need to introduce newer vaccines or alternative intervention to halt the pathogen race toward higher virulence.

Extensive studies in the last few years have identified some of the major viral proteins that contribute directly to the neoplastic transformation and development of tumours, such as the major oncoprotein Meq, MDV-encoded microRNAs, the virus-encoded telomerase RNA (vTR) and viral telomeric repeats (TMRs). While these studies have undoubtedly provided insights into the direct determinants of neoplastic transformation, the role of the majority of other viral proteins may also be critical to the understanding of viral pathogenicity; hence, the development of the vaccine development needs to be explored to ensure better protection of chickens from this deadly disease.

For this Special Issue, we invite submissions that provide deeper insights into important aspects of MDV infection, lytic replication, latency, transformation, latent to lytic switch, reactivation, pathogenesis, diagnostics, immune response to MD, molecular epidemiology, and the evolution of the field strains.

We look forward to your contributions!

Prof. Dr. Sanjay Reddy
Dr. Yongxiu Yao
Prof. Dr. Blanca Lupiani
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Marek’s disease virus
  • oncogenesis
  • host-virus interactions
  • transformation
  • latency
  • MDV pathogenesis

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Published Papers (6 papers)

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Research

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13 pages, 2156 KiB  
Article
Efficient Cross-Screening and Characterization of Monoclonal Antibodies against Marek’s Disease Specific Meq Oncoprotein Using CRISPR/Cas9-Gene-Edited Viruses
by Man Teng, Jin-Ling Liu, Qin Luo, Lu-Ping Zheng, Yongxiu Yao, Venugopal Nair, Gai-Ping Zhang and Jun Luo
Viruses 2023, 15(4), 817; https://doi.org/10.3390/v15040817 - 23 Mar 2023
Cited by 2 | Viewed by 2017
Abstract
Marek’s disease (MD) caused by pathogenic Marek’s disease virus type 1 (MDV−1) is one of the most important neoplastic diseases of poultry. MDV−1-encoded unique Meq protein is the major oncoprotein and the availability of Meq-specific monoclonal antibodies (mAbs) is crucial for revealing MDV [...] Read more.
Marek’s disease (MD) caused by pathogenic Marek’s disease virus type 1 (MDV−1) is one of the most important neoplastic diseases of poultry. MDV−1-encoded unique Meq protein is the major oncoprotein and the availability of Meq-specific monoclonal antibodies (mAbs) is crucial for revealing MDV pathogenesis/oncogenesis. Using synthesized polypeptides from conserved hydrophilic regions of the Meq protein as immunogens, together with hybridoma technology and primary screening by cross immunofluorescence assay (IFA) on Meq-deleted MDV−1 viruses generated by CRISPR/Cas9-gene editing, a total of five positive hybridomas were generated. Four of these hybridomas, namely 2A9, 5A7, 7F9 and 8G11, were further confirmed to secrete specific antibodies against Meq as confirmed by the IFA staining of 293T cells overexpressing Meq. Confocal microscopic analysis of cells stained with these antibodies confirmed the nuclear localization of Meq in MDV-infected CEF cells and MDV-transformed MSB-1 cells. Furthermore, two mAb hybridoma clones, 2A9-B12 and 8G11-B2 derived from 2A9 and 8G11, respectively, displayed high specificity for Meq proteins of MDV−1 strains with diverse virulence. Our data presented here, using synthesized polypeptide immunization combined with cross IFA staining on CRISPR/Cas9 gene-edited viruses, has provided a new efficient approach for future generation of specific mAbs against viral proteins. Full article
(This article belongs to the Special Issue Marek’s Disease Virus)
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18 pages, 4464 KiB  
Article
Role of T Cells in Vaccine-Mediated Immunity against Marek’s Disease
by Mohammad Heidari, Huanmin Zhang, Lakshmi T Sunkara and Syed Mudasir Ahmad
Viruses 2023, 15(3), 648; https://doi.org/10.3390/v15030648 - 28 Feb 2023
Cited by 4 | Viewed by 2315
Abstract
Marek’s disease virus (MDV), a highly cell-associated oncogenic α-herpesvirus, is the etiological agent of T cell lymphomas and neuropathic disease in chickens known as Marek’s disease (MD). Clinical signs of MD include neurological disorders, immunosuppression, and lymphoproliferative lymphomas in viscera, peripheral nerves, and [...] Read more.
Marek’s disease virus (MDV), a highly cell-associated oncogenic α-herpesvirus, is the etiological agent of T cell lymphomas and neuropathic disease in chickens known as Marek’s disease (MD). Clinical signs of MD include neurological disorders, immunosuppression, and lymphoproliferative lymphomas in viscera, peripheral nerves, and skin. Although vaccination has greatly reduced the economic losses from MD, the molecular mechanism of vaccine-induced protection is largely unknown. To shed light on the possible role of T cells in immunity induced by vaccination, we vaccinated birds after the depletion of circulating T cells through the IP/IV injection of anti-chicken CD4 and CD8 monoclonal antibodies, and challenged them post-vaccination after the recovery of T cell populations post-treatment. There were no clinical signs or tumor development in vaccinated/challenged birds with depleted CD4+ or CD8+ T cells. The vaccinated birds with a combined depletion of CD4+ and CD8+ T cells, however, were severely emaciated, with atrophied spleens and bursas. These birds were also tumor-free at termination, with no virus particles detected in the collected tissues. Our data indicated that CD4+ and CD8+ T lymphocytes did not play a critical role in vaccine-mediated protection against MDV-induced tumor development. Full article
(This article belongs to the Special Issue Marek’s Disease Virus)
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30 pages, 5844 KiB  
Article
Contribution of the TCRβ Repertoire to Marek’s Disease Genetic Resistance in the Chicken
by Cari J. Hearn and Hans H. Cheng
Viruses 2023, 15(3), 607; https://doi.org/10.3390/v15030607 - 22 Feb 2023
Cited by 1 | Viewed by 1935
Abstract
Marek’s disease (MD) is a lymphoproliferative disease of chickens induced by Marek’s disease virus (MDV), an oncogenic α-herpesvirus. MDV has increased in virulence, prompting continued efforts in both improved vaccines and enhanced genetic resistance. Model pairs of genetically MD-resistant and MD-susceptible chickens that [...] Read more.
Marek’s disease (MD) is a lymphoproliferative disease of chickens induced by Marek’s disease virus (MDV), an oncogenic α-herpesvirus. MDV has increased in virulence, prompting continued efforts in both improved vaccines and enhanced genetic resistance. Model pairs of genetically MD-resistant and MD-susceptible chickens that were either MHC-matched or MHC-congenic allowed characterization of T cell receptor (TCR) repertoires associated with MDV infection. MD-resistant chickens showed higher usage of Vβ-1 TCRs than susceptible chickens in both the CD8 and CD4 subsets in the MHC-matched model, and in the CD8 subset only in the MHC-congenic model, with a shift towards Vβ-1+ CD8 cells during MDV infection. Long and short read sequencing identified divergent TCRβ loci between MHC-matched MD-resistant and MD-susceptible chickens, with MD-resistant chickens having more TCR Vβ1 genes. TCR Vβ1 CDR1 haplotype usage in MD-resistant x MD-susceptible F1 birds by RNAseq indicated that the most commonly used CDR1 variant was unique to the MD-susceptible line, suggesting that selection for MD resistance in the MHC-matched model optimized the TCR repertoire away from dominant recognition of one or more B2 haplotype MHC molecules. Finally, TCR downregulation during MDV infection in the MHC-matched model was strongest in the MD-susceptible line, and MDV reactivation downregulated TCR expression in a tumor cell line. Full article
(This article belongs to the Special Issue Marek’s Disease Virus)
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18 pages, 3792 KiB  
Article
A New Strategy for Efficient Screening and Identification of Monoclonal Antibodies against Oncogenic Avian Herpesvirus Utilizing CRISPR/Cas9-Based Gene-Editing Technology
by Man Teng, Zi-Yu Zhou, Yongxiu Yao, Venugopal Nair, Gai-Ping Zhang and Jun Luo
Viruses 2022, 14(9), 2045; https://doi.org/10.3390/v14092045 - 14 Sep 2022
Cited by 4 | Viewed by 2596
Abstract
Marek’s disease virus (MDV) is an important oncogenic α-herpesvirus that induces Marek’s disease (MD), characterized by severe immunosuppression and rapid-onset T-cell lymphomas in its natural chicken hosts. Historically, MD is regarded as an ideal biomedical model for studying virally induced cancers. Monoclonal antibodies [...] Read more.
Marek’s disease virus (MDV) is an important oncogenic α-herpesvirus that induces Marek’s disease (MD), characterized by severe immunosuppression and rapid-onset T-cell lymphomas in its natural chicken hosts. Historically, MD is regarded as an ideal biomedical model for studying virally induced cancers. Monoclonal antibodies (mAbs) against viral or host antigenic epitopes are crucial for virology research, especially in the exploration of gene functions, clinical therapy, and the development of diagnostic reagents. Utilizing the CRISPR/Cas9-based gene-editing technology, we produced a pp38-deleted MDV-1 mutant—GX0101Δpp38—and used it for the rapid screening and identification of pp38-specific mAbs from a pool of MDV-specific antibodies from 34 hybridomas. The cross-staining of parental and mutated MDV plaques with hybridoma supernatants was first performed by immunofluorescence assay (IFA). Four monoclonal hybridomas—namely, 4F9, 31G7, 34F2, and 35G9—were demonstrated to secrete specific antibodies against MDV-1’s pp38 protein, which was further confirmed by IFA staining and confocal analysis. Further experiments using Western blotting, immunoprecipitation (IP), liquid chromatography–tandem mass spectrometry (LC–MS/MS), and immunohistochemistry (IHC) analysis demonstrated that the pp38-specific mAb 31G7 has high specificity and wide application potential for further research in MD biology. To the best of our knowledge, this is the first demonstration of the use of CRISPR/Cas9-based gene-editing technology for efficient screening and identification of mAbs against a specific viral protein, and provides a meaningful reference for the future production of antibodies against other viruses—especially for large DNA viruses such as herpesviruses. Full article
(This article belongs to the Special Issue Marek’s Disease Virus)
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10 pages, 1625 KiB  
Article
Pathogenicity and Pathotype Analysis of Henan Isolates of Marek’s Disease Virus Reveal Long-Term Circulation of Highly Virulent MDV Variant in China
by Man Teng, Lu-Ping Zheng, Hui-Zhen Li, Sheng-Ming Ma, Zhi-Jian Zhu, Shu-Jun Chai, Yongxiu Yao, Venugopal Nair, Gai-Ping Zhang and Jun Luo
Viruses 2022, 14(8), 1651; https://doi.org/10.3390/v14081651 - 27 Jul 2022
Cited by 9 | Viewed by 2801
Abstract
In recent years, outbreaks of Marek’s disease (MD) have been frequently reported in vaccinated chicken flocks in China. Herein, we have demonstrated that four Marek’s disease virus (MDV) isolates, HN502, HN302, HN304, and HN101, are all pathogenic and oncogenic to hosts. Outstandingly, the [...] Read more.
In recent years, outbreaks of Marek’s disease (MD) have been frequently reported in vaccinated chicken flocks in China. Herein, we have demonstrated that four Marek’s disease virus (MDV) isolates, HN502, HN302, HN304, and HN101, are all pathogenic and oncogenic to hosts. Outstandingly, the HN302 strain induced 100% MD incidence, 54.84% mortality, and 87.10% tumor incidence, together with extensive atrophy of immune organs. Pathotyping of HN302 was performed in comparison to a standard very virulent (vv) MDV strain Md5. We found that both CVI988 and HVT vaccines significantly reduced morbidity and mortality induced by HN302 or Md5 strains, but the protection indices (PIs) provided by these two vaccines against HN302 were significantly lower (27.03%) or lower (33.33%) than that against Md5, which showed PIs of 59.89% and 54.29%, respectively. These data suggested that HN302 possesses a significant higher virulence than Md5 and at least could be designated as a vvMDV strain. Together with our previous phylogenetic analysis on MDV-1 meq genes, we have presently suggested HN302 to be a typical highly virulent MDV variant belonging to an independent Chinese branch. To our knowledge, this is the first report to provide convincible evidence to identify a pathogenic MDV variant strain with a higher virulence than Md5 in China, which may have emerged and circulating in poultry farms in China for a long time and involved in the recent MD outbreaks. Full article
(This article belongs to the Special Issue Marek’s Disease Virus)
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Review

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16 pages, 311 KiB  
Review
The Importance of the Bursa of Fabricius, B Cells and T Cells for the Pathogenesis of Marek’s Disease: A Review
by Karel A. Schat
Viruses 2022, 14(9), 2015; https://doi.org/10.3390/v14092015 - 12 Sep 2022
Cited by 7 | Viewed by 2934
Abstract
The importance of the bursa of Fabricius (BF) for the pathogenesis of Marek’s disease (MD) has been studied since the late 1960’s. In this review, the results of these studies are analyzed in the context of the developing knowledge of the immune system [...] Read more.
The importance of the bursa of Fabricius (BF) for the pathogenesis of Marek’s disease (MD) has been studied since the late 1960’s. In this review, the results of these studies are analyzed in the context of the developing knowledge of the immune system of chickens and the pathogenesis of MD from 1968 to 2022. Based on the available techniques to interfere with the development of the BF, three distinct periods are identified and discussed. During the initial period between 1968 and 1977, the use of neonatal bursectomy, chemical methods and irradiation were the main tools to interfere with the B lymphocyte development. The application of these techniques resulted in contradictory results from no effects to an increase or decrease in MD incidence. Starting in the late 1970’s, the use of bursectomy in 18-day-old embryos led to the development of the “Cornell model” for the pathogenesis of MD, in which the infection of B lymphocytes is an important first step in MD virus (MDV) replication causing the activation of thymus-derived lymphocytes (T cells). Following this model, these activated T cells, but not resting T cells, are susceptible to MDV infection and subsequent transformation. Finally, B-cell knockout chickens lacking the J gene segment of the IgY heavy chain gene were used to further define the role of the BF in the pathogenesis of MD. Full article
(This article belongs to the Special Issue Marek’s Disease Virus)
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