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Title: Immune modulation by Marek's Disease Virus
Author: Boodhoo, Nitish
ISNI:       0000 0004 7966 7704
Awarding Body: University of Reading
Current Institution: University of Reading
Date of Award: 2019
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The emergence of highly pathogenic Marek's Disease Virus (MDV) strains, defined by acute onset of Marek's Disease (MD), has led to renewed emphasis for understanding host-pathogen interaction. Little is known about the mechanism of MDV replication due to its highly cell associated nature. An association between lipid metabolite remodelling and MDV infection in MD-susceptible lines of chickens based on atherosclerotic plaque formation has been previously established. Immunosuppressive lipid can impair immune system cell function; limit activation, infiltration into active sites of virus replication and modulate recognition of infected cells. Therefore the correlates of immune protection are unknown as antigen specific T cell responses against MDV have yet to be reported. Our primary objective was to use a pathway interference approach to study lipid biosynthesis. We demonstrate that infection with MDV leads to induction of fatty acid synthesis that can contribute towards eicosanoid synthesis in a COX-2 dependent manner. Specifically we identified induction of prostaglandin E2 (PGE2) biosynthesis in MDV infected CEFs and demonstrate a dependence for replication. Eicosanoids are well characterised for their ability to modulate immune system cell function including T cells. The second objective was to evaluate in vivo T cell responses or cell mediated immunity against MDV in both the MD-resistant (B21) and MD-susceptible (B19) lines of chicken. We demonstrate detection of a T cell response against MDV with the eliciting response directed against viral MEQ and pp38 in chickens that were either challenged (RB1B), vaccine (CVI988/RISPENS)-challenged (RB1B) or vaccine-boosted but not mock infected. CD4+TCRvβ1+ cells were the main responding T cell subset recognising the identified immunodominant pp38 epitopes (pp385-20, pp38161-176 and pp38171-186) in all the MDresistant (B21) and MD-susceptible (B19) lines of chicken. Induction of transcripts for cytokines (IL-2, IL-4 and IL-10) and CD4+ T cell proliferation was observed in a peptide specific manner. However, challenge impaired the ability of T cell to degranulate based on cell surface translocation of CD107a; although peptide specific induction for transcript of perforin and granzyme B can be detected. Taken together we demonstrate that T cell responses against MDV are limited and may be linked to lipid induced biosynthesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral