What is MDV?

Marek's Disease (MD)

Marek's disease (MD) of chickens is an infectious lymphoproliferative disease caused by Marek's disease virus (MDV). Nerve enlargement, immunosuppression and visceral tumors formed by transformed T cells are the main clinical manifestations of the disease. The disease is prevalent in chicken farming areas around the world, and causes huge economic losses to the poultry industry, seriously threatening the healthy development of global poultry farming. In recent years, with the further expansion of the scale of poultry farming and the successive outbreak of highly virulent Marek's strains in many countries and regions in the world, new challenges have been brought to the prevention and control of the disease.

The hosts infected by MDV include chickens, turkeys, pheasants, and quails. It does not transmit vertically, but mainly spreads through direct or indirect airborne contact via shed epithelial cells from feather follicles of infected and carrier chickens. MDV can survive in feather follicle epithelial cells for 4-18 months under normal temperature conditions, which is the main reason for MDV's strong transmission capability and severe harm. Clinically, chicks infected early have a long incubation period, generally developing symptoms after 3-4 weeks, with the most severe onset occurring at 2-3 months. The mortality rate in non-immunized flocks is usually 10%-30%, sometimes reaching 60%-80% or even higher.

After MDV infection, clinical manifestations include depression and weight loss; peripheral nerve damage causing affected chickens to assume a typical splayed-leg posture with unilateral wing drooping; visual impairment; nodular lesions in skin follicles; and tumors in various internal organs, ultimately leading to mass mortality of chickens. Furthermore, early infection can cause atrophy of the host's immune organs, leading to immunosuppression, which triggers immune failure against other infectious diseases, resulting in immeasurable indirect economic losses.

MD was the first tumor disease that could be prevented by vaccination using a naturally isolated, non-pathogenic MDV strain. The earliest vaccine developed was the turkey herpesvirus (HVT) vaccine, which effectively controlled the disease at the time and significantly reduced the economic losses caused by MD. However, subsequently more virulent MDV strains appeared in flocks vaccinated with HVT alone. Thereafter, bivalent vaccine based on the combination of HVT and SB-1 has been developed to enhance protection. It is to be noted that successive generations of MD vaccines used throughout the world on a very large scale are exerting immune pressure on the virus, which is still evolving in response and becoming more virulent. This may eventually lead to failure of the vaccines to protect from the disease.

Figure 1. Increasing average virulence of MDV field strains and introduction of the different MDV vaccines over the past decades in the USA
(Source: Bertzbach LD, et al. 2020)

Important Functional Genes of MDV

Due to the large size of the MDV genome, many genes and their encoded proteins remain functionally unverified. Among the genes whose functions have been explored, they are mainly divided into two categories: one consists of MDV-specific genes, such as Meq, pp38, and pp24; the other consists of genes with homologous characteristics to alpha-herpesviruses, whose encoded proteins include gB, gC, gD, and gH.

The Meq oncogene is one of the most extensively studied MDV genes, encoded by the RLORF7 gene and containing 339 amino acids. The Meq gene can encode a basic leucine zipper transcription factor that facilitates dimerization with the cJun oncoprotein (cJun-Meq) or with itself (Meq-Meq) and interferes with the expression of apoptotic factors and virus-related genes. Studies have reported that these dimerization phenomena bind to cell cycle control-related factors and MERE promoter sites, upregulating their own transcriptional expression. In MDV-induced T-cell lymphoma events, MDV regulates host and viral gene expression modifications and plays a crucial role in conjunction with other transcription factors. Abundant expression of the Meq gene can be observed in chicken tumor events caused by MD and in lysed infected T lymphocytes. However, when poultry are infected with Meq-deficient MDV strains, tumor events do not develop, and viral telomere integration is not observed in primary immune tissues. The Meq gene belongs to the MDV-1-specific gene sequence and is not present in MDV-2 and HVT, so these two serotypes of MDV do not express cancer-related proteins during infection, replication, or latency.

The vIL-8 gene is a chicken IL-8 homolog located in the long repeat region of MDV and contains 134 amino acids. The vIL-8 gene is another MDV gene that contributes to tumorigenesis and is encoded in the UL region of the genome. vIL-8 is a chemokine for chicken peripheral blood mononuclear cells, and the chemotactic cells include lymphocytes, monocytes, and macrophages. Studies have shown that vIL-8 can recruit target cells for MDV lytic infection and MDV latent infection by chemotaxis of B lymphocytes, CD4+ and CD25+ T lymphocytes.

The vTR gene is a viral homolog of the chicken telomerase RNA subunit (TR) located within the IRL/TRL region of the MDV genome. The high homology between vTR and chicken TR is interpreted as evidence of selective pressure maintaining the TR sequence. Studies suggest that vTR expression may have anti-apoptotic properties in latently infected cells. MDV strains with vTR gene deletion (with atypical telomeric repeats) are severely impaired in their ability to induce lymphomas in vivo, with significantly reduced tumor incidence and size, indicating that this gene is tumor-related. Additionally, the vTR gene has synergistic tumorigenic effects with virus-encoded sRNA.

Figure 2. MDV genes and gene products involved in pathogenesis and/or immune evasion
(Source: Osterrieder N, et al. 2006)

Research on Interactions between MDV and Other Poultry Viruses

Research on Interactions between MDV and Other Poultry Viruses

Co-infection of MDV with other poultry-derived immunosuppressive viruses generally leads to more severe immunosuppression in poultry. On one hand, MDV-induced immunosuppression impairs the host's ability to generate effective immune responses against co-infecting viruses, resulting in increased viral replication, more severe disease symptoms, and higher mortality rates. On the other hand, other poultry-derived immunosuppressive viruses such as IBDV, CIAV, and ARV can compete or exert cytolytic effects on lymphocyte populations, weakening MD symptoms through lymphoid organ atrophy and depletion, but similarly reducing vaccine protection efficacy.

Additionally, co-infection between MDV and REV leads to the integration of REV's LTR (Long terminal repeat) sequences into MDV's common integration sites, resulting in genetic recombination. For example, co-infection of MDV with ALV and REV results in synergistic viral replication, exacerbating disease severity and increasing susceptibility to secondary infections. Co-infection of MDV with CIAV makes the anemia symptoms caused by CIAV more severe and increases mortality rates in infected chickens. Co-infection of MDV with IBDV and ARV suppresses tumor formation and creates mutual inhibition of MDV replication, but similarly reduces MD vaccine protection efficacy.

MDV Antibodies

MDV Antigens