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  • Review Article
  • Published:

Marek's disease virus: from miasma to model

Nature Reviews Microbiology volume 4, pages 283–294 (2006)Cite this article

Key Points

  • Marek's disease (MD) is a widespread, herpesvirus-induced neoplastic disease in the domestic chicken that is caused by Marek's disease virus (MDV). The main characteristic of MD is T-cell lymphomagenesis with dissemination of transformed cells preferentially to visceral organs and skeletal muscle, where solid tumours develop. Over the years, the virus has changed its tropism with a concomitant change in the clinical picture of MD, which now also results in oedema and widespread damage of the brain and central nervous system, ultimately leading to paralysis and death.

  • Three stages of MD infection can be distinguished. During the cytolytic phase, MDV enters the organism by inhalation from the environment, undergoes a first round of replication and disseminates to lymphoid organs; the virus then enters the latent stage of infection, predominantly in CD4+ T cells; finally, T-cell transformation, lymphomagenesis and spread of the lymphoid neoplasia ensues.

  • MDV encodes approximately 100 gene products, most of which have high similarity to those of related α-herpesviruses. Among the proteins unique to MDV are secreted factors, such as a viral homologue of chicken interleukin 8 (vIL-8) and a secreted protein with homology to pancreatic lipases (vLIP). These two secreted proteins, along with secreted glycoprotein C (gC), have important roles in the initial stages of infection, probably through cell signalling and the attraction of target cells.

  • MDV lymphomagenesis is a complex process, which appears to require robust lytic replication to ensure that the virus reaches activated T cells where latency and transformation commence. MDV-induced tumours, which are oligoclonal or monoclonal, mainly consist of latently infected T cells harbouring the integrated viral genome.

  • Transformation requires a basic leucine zipper protein, Meq, which is a member of the Jun/Fos family of oncoproteins. Meq possesses transforming properties in vitro, and a meq-negative MDV is unable to cause tumours.

  • MDV also encodes a functional and highly active viral telomerase RNA (vTR), which is expressed in the lytic, latent and tumour phase of infection and was shown to be required for efficient lymphomagenesis and to possess transforming properties.

  • MD is efficiently controlled by immunization using modified-live-virus vaccines. Despite the success of comprehensive vaccination, new virus variants are emerging which are able to break vaccine protection and exhibit increased virulence. Therefore, MD poses a constant threat to chicken populations worldwide.

  • Current research focuses on the elucidation of MD pathogenesis and the rational design and engineering of novel vaccines. For both these main areas of MD research, the generation of infectious virus clones and their mutagenesis in Escherichia coli are instrumental.

Abstract

Marek's disease virus (MDV) is an oncogenic herpesvirus that causes various clinical syndromes in its natural host, the chicken. MDV has long been of interest as a model organism, particularly with respect to the pathogenesis and immune control of virus-induced lymphoma in an easily accessible small-animal system. Recent advances in MDV genetics and the determination of the chicken genome sequence, aided by functional genomics, have begun to dramatically increase our understanding not only of lytic MDV replication, but also of the factors and mechanisms leading to latency and tumour formation. This new information is helping to elucidate cellular signalling pathways that have undergone convergent evolution and are perturbed by different viruses, and emphasizes the value of MDV as a comparative biomedical model. Furthermore, the door is now open for rational and efficient engineering of new vaccines against one of the most important and widespread infectious diseases in chickens.

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Figure 1: Organization of the Marek's disease virus (MDV) genome.
Figure 2: Manipulating infectious Marek's disease virus (MDV) bacterial artificial chromosome (BAC) clones.
Figure 3: Genes and gene products essential for Marek's disease virus (MDV) replication in vitro and/or in vivo.
Figure 4: Transformation by Marek's disease virus (MDV) and the roles of Meq and vTR.

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Acknowledgements

We would like to thank the MDV community for many stimulating discussions and the privilege of being their colleagues. The past eight years of MDV research have been a rewarding experience. Special thanks go to H. Hunt and S. Burgess for critically reading the manuscript. Research on Marek's disease in our laboratory is supported by funds provided by the College of Veterinary Medicine at Cornell University and grants awarded through the National Research Initiative of the United States Department of Agriculture.

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  1. Jeremy P. Kamil

    Present address: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, 250 Longwood Avenue, Boston, Massachusetts, 02115, USA

  2. B. Karsten Tischer

    Present address: Institut für Infektionsmedizin, Christian-Albrechts-Universität zu Kiel, 24159, Kiel, Germany

Authors and Affiliations

  1. Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, New York, 14853, USA

    Nikolaus Osterrieder, Daniel Schumacher & Sascha Trapp

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Correspondence to Nikolaus Osterrieder.

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Glossary

Polyneuritis

General inflammation of nerves.

Visceral lymphoma

Solid neoplasms in organs of the abdomen such as heart, liver, kidney or gonads that are characterized by an accumulation of transformed lymphocytes and immune cells.

Neoplastic disease

A disease involving uncontrolled cell growth, a cancer.

Lymphomagenesis

Process involving the transformation and expansion of lymphocytes, resulting in a cancer of the affected cells.

CD4+ T cells

A subpopulation of T cells that express the CD4 receptor. These cells aid in immune responses and are therefore referred to as T helper cells.

Macrophages

Cells of the mononuclear phagocyte lineage that are responsible for phagocytosis of foreign material.

Dendritic cells

(DCs). 'Professional' antigen-presenting cells that are found in the T-cell areas of lymphoid tissues and as minor cellular components in most tissues. They have a branched or dendritic morphology and are the most potent stimulators of T-cell responses.

Bacterial artifical chromosome

(BAC). A prokaryotic cloning vector derived from a single-copy or low-copy-number mini-F plasmid that can stably maintain a large DNA insert (average size 150–300 kb) and can be propagated in Escherichia coli.

Cosmid

A plasmid cloning vector containing two cohesive (cos) ends from phage λ and one or more selectable markers that allow efficient cloning and amplification of large DNA fragments (40–50 kb) in Escherichia coli.

Bursa of Fabricius

The primary lymphoid organ in which B-cell maturation occurs in the chicken.

CD4−CD8− T cells

T cells that express neither CD4 nor CD8 on their surface. These cells represent approximately 1–5% of αβ T cells and have been associated with immunoregulatory and immunosuppressive functions.

CD8+ T cells

A subpopulation of T cells that express the CD8 receptor. CD8+ cells recognize antigens that are presented on the surface of host cells by MHC class I molecules, leading to their destruction, and are therefore also known as cytotoxic T cells.

Immediate-early genes

Those herpesvirus genes encoding important transactivators that initiate and maintain the cascade-like expression of herpesvirus genes that also comprises early (mostly enzymes for DNA replication) and late (structural) genes.

Transactivators

Proteins, such as the immediate-early genes or Meq, that function by enhancing the expression of other viral or cellular genes.

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Osterrieder, N., Kamil, J., Schumacher, D. et al. Marek's disease virus: from miasma to model. Nat Rev Microbiol 4, 283–294 (2006). https://doi.org/10.1038/nrmicro1382

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