Title

Mechanisms of Genetic Resistance and Neoplastic Transformation in Marek's Disease

Advisor

Burgess, Shane C.

Committee Member

Sharif, Shayan

Committee Member

Pharr, Gregory Todd

Committee Member

Pinchuk, Lesya M.

Committee Member

Buza, Joram J.

Date of Degree

1-1-2011

Original embargo terms

MSU Only Indefinitely

Document Type

Dissertation - Open Access

Major

Veterinary Medical Science

Degree Name

Doctor of Philosophy

College

College of Veterinary Medicine

Abstract

Marek’s disease (MD) of chickens is an economically important, contagious, neoplastic disease caused by Gallid herpesvirus type 2. All chicken are susceptible to MDV infection and neoplastic transformation, but, only susceptible genotypes develop gross lymphomas. Lymphomas regress in resistant genotypes from 21 days post infection (dpi). The central aims of this study were to understand the mechanisms of non-MHC associated genetic resistance and the molecular pathways of neoplastic transformation. We hypothesized that, a) in resistant chickens at 21 dpi the tissue microenvironment is compatible with cell mediated immunity but in susceptible lines antagonistic to cell mediated immunity, b) resistant genotypes present immunogenic peptides on their MHC class I which while the peptides presented by susceptible genotypes do not induce CTL immunity resulting in tumor progression. We used inbred, MHC homozygous MD resistant (L6) and susceptible (L7) chickens and reductionist methods to test our hypotheses. Our results indicated that the tumor microenvironment is pro T-regulatory in both resistant and susceptible genotypes, and, the host immune response (pro Th-1 in resistant and pro Th-2/T-reg in susceptible) influences the tumor regression or progression. Statistical analysis of MHC class I bound peptides from resistant and susceptible genotypes confirmed that they present the same peptides and perhaps genes outside the MHC locus play an important role in determining resistance. Next, using Systems Biology tools like genomics, proteomics, Gene Ontology modeling and pathway analysis we compared the transcriptome and proteome of neoplastically transformed cells (CD30hi) and non-neoplastically transformed cells (CD30lo) which are the two components of tumor microenvironment. We demonstrated that: a) in situ, CD30lo cells are pre-neoplastic and the proteome involved in transformation and potential mechanisms that may be controlled by MDV oncogene Meq; b) Meq can drive a feed forward loop that induces CD30 transcription and overexpression, increased CD30 signaling, which then activates NFêB and, in turn, increases Meq transcription; c) Meq transcriptional repression or activation from the CD30 promoter generally correlates with a polymorphism in the CD30 promoter between MD-resistant and -susceptible chicken genotypes and so a herpesvirus has evolved to utilize NFêB as a direct transcriptional activator for its oncogene.

URI

https://hdl.handle.net/11668/19153

Comments

Meq||Hodgkin's Lymphoma||CD30||Marek's Disease||tumor resistance||lymphoma

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