Immune modulation by Marek's Disease Virus

Abstract

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.