Selection of a Recombinant Marek's Disease Virus In Vivo Through Expression of the Marek's EcoRI-Q (Meq)–Encoded Oncoprotein: Characterization of an rMd5-Based Mutant Expressing the Meq of Strain RB-1B

Kumar, Pankaj; Dong, Huimin; Lenihan, Dawn; Gaddamanugu, Syamsundar; Katneni, Upendra; Shaikh, Shireen; Tavlarides-Hontz, Phaedra; Reddy, Sanjay M.; Peters, Wachen; Parcells, Mark S.

doi:10.1637/9955-100611-reg.1

Cited by 4 publications

(5 citation statements)

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“…A detailed understanding on the geographic dominance of different MD viral strains is also required for effective vaccine development. Biochemically, changes in meq have been associated with increased transcriptional activation [ 55 , 56 ], increased invasiveness of cells expressing meq isoforms, and most recently, changes in tumor composition [ 57 ]. How these particular mutations directly contribute to MDV changes in virulence await further mutant construction and characterization.…”

Section: Resultsmentioning

confidence: 99%

Positive Selection Drives Rapid Evolution of the meq Oncogene of Marek’s Disease Virus

Padhi

Parcells

2016

PLoS ONE

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Marek’s disease (MD), caused by Marek’s disease virus (MDV), a poultry-borne alphaherpesvirus, is a devastating disease of poultry causing an estimated annual loss of one billion dollars to poultry producers, worldwide. Despite decades of control through vaccination, MDV field strains continue to emerge having increased virulence. The evolutionary mechanism driving the emergence of this continuum of strains to increased MDV virulence, however, remains largely enigmatic. Increase in MDV virulence has been associated with specific amino acid changes within the C-terminus domain of Mareks’s EcoRI-Q (meq)-encoded oncoprotein. In this study, we sought to determine whether the meq gene has evolved adaptively and whether past vaccination efforts have had any significant effect on the reduction or increase of MDV diversity over time. Our analysis suggests that meq is estimated to be evolving at a much faster rate than most dsDNA viruses, and is comparable with the evolutionary rate of RNA viruses. Interestingly, most of the polymorphisms in meq gene appear to have evolved under positive selection and the time of divergence at the meq locus coincides with the period during which the poultry industry had undergone transitions in management practices including the introduction and widespread use of live attenuated vaccines. Our study has revealed that the decades-long use of vaccines did not reduce MDV diversity, but rather had a stimulating effect on the emergence of field strains with increased genetic diversity until the early 2000s. During the years 2004–2005, there was an abrupt decline in the genetic diversity of field isolates followed by a recovery from this bottleneck in the year 2010. Collectively, these data suggest that vaccination seems to not have had any effect on MDV eradication, but rather had a stimulating effect on MDV emergence through adaptation.

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Section: Resultsmentioning

confidence: 99%

Positive Selection Drives Rapid Evolution of the meq Oncogene of Marek’s Disease Virus

Padhi

Parcells

2016

PLoS ONE

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“…Of these, Meq (Jones et al, 1992), vIL-8 (Parcells et al, 2001) and pp38 (Cui et al, 1991) genes are most important in viral oncogenesis of serotype-1 MDVs (Wozniakowski et al, 2010;Tian et al, 2011). Mutations in nucleotide sequences of Meq and vIL-8 genes are most important in evolution of serotype-1 MDVs from less virulent to most virulent forms that result in high mortality rates with infiltration of lymphoblastoid cells in different visceral organs (Silva, 1992;Shamblin et al, 2004;Tian et al, 2011;Kumar et al, 2012;Gong et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization and phylogenetic analysis of oncogenes from virulent serotype-1 Marek's disease virus in India

Prathibha¹,

Sreedevi²,

Kumar³

et al. 2018

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Marek's disease (MD) is one of the most important neoplastic diseases of poultry caused by Marek's disease virus (MDV), an oncogenic avian herpes virus, which is responsible for great economic losses to the poultry industry worldwide. Inspite of the usage of HVT and bivalent vaccines in the poultry flocks, MD continues to be a major threat to the poultry industry in India. In the present study, MD outbreaks were reported in poultry farms from different regions of Andhra Pradesh, India. The postmortem examination of dead birds showed presence of lymphomas in different visceral organs suggestive of virulent oncogenic MDVs. Histopathological examination revealed infiltration of pleomorphic lymphoblastoid cells typical of MD. The blood and tissue samples were collected and PCR was standardized targeting a 132 bp tandem repeat region specific for serotype-1 MD viruses. Further, the characterization of the oncogenes i.e. Meq and viral interleukin 8 (vIL-8) was carried out by PCR and nucleotide sequencing. The sequence analysis of Meq gene of different clinical cases from India revealed >99 % homology with RB1B (very virulent) and GA (virulent) strains and that of vIL-8 gene showed >99 % identity with virulent strains LS and LMS. Phylogenetic analysis of oncogenes was carried out with other available sequences in the GenBank. Finally, we conclude that MDV strains obtained in the present outbreaks in India could be designated as virulent or very virulent pathotypes based on nucleotide, amino acid and phylogenetic analysis of the viruses.

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“…The vMDV meq (JM/102W) harbors a 177 bp insertion or duplication of a proline-rich (PRR) domain [40] located in the transactivation domain ( Fig 1A). This insertion increased the copy number of the PRR, which exerts a transrepression effect [41,42]. The higher virulent forms vvMeq and vv+Meq showed higher disease incidence rates and enhanced oncogenesis compared to the less virulent pathotypes (Fig 2B-2D).…”

Section: Plos Pathogensmentioning

confidence: 96%

“…Kumar and colleagues previously inserted meq of RB-1B into rMd5 (both vv strains), in which the meq only differs in three amino acid positions. This exchange altered the phenotype of the resulting virus in the subtle way and allowed the establishment of tumors cell lines (UD36-38) which could not be achieved with the parental rMd5 [41]. Tumors induced by the recombinant showed similar cellular expression profiles to rMd5 tumors, suggesting that the context of the strain encoding the Meq protein plays an important role in pathogenesis.…”

Section: Plos Pathogensmentioning

confidence: 99%

Distinct polymorphisms in a single herpesvirus gene are capable of enhancing virulence and mediating vaccinal resistance

et al. 2020

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Modified-live herpesvirus vaccines are widely used in humans and animals, but field strains can emerge that have a higher virulence and break vaccinal protection. Since the introduction of the first vaccine in the 1970s, Marek’s disease virus overcame the vaccine barrier by the acquisition of numerous genomic mutations. However, the evolutionary adaptations in the herpesvirus genome responsible for the vaccine breaks have remained elusive. Here, we demonstrate that point mutations in the multifunctional meq gene acquired during evolution can significantly alter virulence. Defined mutations found in highly virulent strains also allowed the virus to overcome innate cellular responses and vaccinal protection. Concomitantly, the adaptations in meq enhanced virus shedding into the environment, likely providing a selective advantage for the virus. Our study provides the first experimental evidence that few point mutations in a single herpesviral gene result in drastically increased virulence, enhanced shedding, and escape from vaccinal protection.

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Selection of a Recombinant Marek's Disease Virus In Vivo Through Expression of the Marek's EcoRI-Q (Meq)–Encoded Oncoprotein: Characterization of an rMd5-Based Mutant Expressing the Meq of Strain RB-1B

Cited by 4 publications

References 44 publications

Positive Selection Drives Rapid Evolution of the meq Oncogene of Marek’s Disease Virus

Positive Selection Drives Rapid Evolution of the meq Oncogene of Marek’s Disease Virus

Molecular characterization and phylogenetic analysis of oncogenes from virulent serotype-1 Marek's disease virus in India

Distinct polymorphisms in a single herpesvirus gene are capable of enhancing virulence and mediating vaccinal resistance

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