Marek's disease virus-encoded Meq gene is involved in transformation of lymphocytes but is dispensable for replication

Abstract

Marek's disease virus (MDV) causes an acute lymphoproliferative disease in chickens, resulting in T cell lymphomas in visceral organs and peripheral nerves. Earlier studies have determined that the repeat regions of oncogenic serotype 1 MDV encode a basic leucine zipper protein, Meq, which structurally resembles the Jun͞Fos family of transcriptional activators. Meq is consistently expressed in MDV-induced tumor cells and has been suggested as the MDVassociated oncogene. To study the function of Meq, we have generated an rMd5⌬Meq virus by deleting both copies of the meq gene from the genome of a very virulent strain of MDV. Growth curves in cultured fibroblasts indicated that Meq is dispensable for in vitro virus replication. In vivo replication in lymphoid organs and feather follicular epithelium was also not impaired, suggesting that Meq is dispensable for lytic infection in chickens. Reactivation of the rMd5⌬Meq virus from peripheral blood lymphocytes was reduced, suggesting that Meq is involved but not essential for latency. Pathogenesis experiments showed that the rMd5⌬Meq virus was fully attenuated in chickens because none of the infected chickens developed Marek's disease-associated lymphomas, suggesting that Meq is involved in lymphocyte transformation. A revertant virus that restored the expression of the meq gene, showed properties similar to those of the parental virus, confirming that Meq is involved in transformation but not in lytic replication in chickens.

Interaction of MEQ protein and C-terminal-binding protein is critical for induction of lymphomas by Marek’s disease virus

“…A revertant pRB-1B-Ct22 virus, in which the wild-type sequence was restored, regained its ability to induce lymphomas, further confirming that interaction with CtBP is critical for transformation. Although previous studies have implicated MEQ in MDV oncogenicity (6,25), this study demonstrates a potential molecular mechanism for induction of T cell tumors by MDV. A direct role for MEQ-CtBP interaction in MDV oncogenicity may also highlight the convergent evolution of molecular mechanisms in cell transformation by oncogenic herpesviruses.…”

“…MEQ, encoded within the repeat regions of the MDV genomes of serotype 1 strains of MDV, is expressed in all tumor cells and lymphoblastoid cell lines derived from lymphomas (25). A direct role of MEQ in the induction of tumors has been recently demonstrated by using MEQ-deletion mutants of MDV, which failed to induce tumors (6).…”

“…A fundamental understanding of the molecular mechanisms of MD oncogenesis is therefore important to the development of more sustainable control strategies and to the cessation of the continuing trend in the evolution of MDV virulence (2). The transcriptional regulator MEQ (MDV EcoRI Q) is considered to be the major viral oncoprotein of MDV (6). MEQ has a nuclear distribution and can induce transcriptional activation or repression depending on its dimerization partner and DNAbinding specificity (7).…”

Addition of a UL5 helicase-primase subunit point mutation eliminates bursal–thymic atrophy of Marek's disease virus ∆Meq recombinant virus but reduces vaccinal protection

“…In addition to BTA, another trait characteristic of low passage ΔMeq is the vigorous in vivo replication of ΔMeq during early cytolytic replication. This characteristic was previously described and is apparent in this study as well (Lupiani et al, 2004;Dunn & Silva, 2012). Due to loss of vigorous in vivo replication following serial passage of ΔMeq, it was postulated this high replication within lymphoid organs was the cause of BTA.…”

Chicks and single-nucleotide polymorphisms: an entrée into identifying genes conferring disease resistance in chicken

“…MDV Meq is a bZIP transcription factor and the likely MDV oncogene (Jones et al 1992;Lupiani et al 2004), suggesting that one pathway for resistance is the inability of Meq to regulate the transcription of specific genes in individuals resistant to MD, thereby failing to initiate transformation. Therefore, it is of interest to define DNA-binding sites and the genes that are directly regulated by Meq.…”