Innate patterning of the immune response to Marek's disease virus (MDV) during pathogenesis and vaccination
Date
2015
Authors
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Publisher
University of Delaware
Abstract
Marek's disease (MD) is a lymphoproliferative disease of chickens induced by an alphaherpesvirus, Marek's disease virus (MDV). MD is the first neoplastic disease to be effectively controlled by vaccination. MD vaccines are not sterilizing, but reduce early viremia and subsequent tumor formation caused by pathogenic strains. In spite of vaccines being in use since the early 1970s, the molecular mechanisms of vaccine protection are poorly understood. The predominant thought is that MD vaccines elicit continual anti-viral cytotoxic T-cell and antibody responses via a low-level of replication, a limited establishment of latency, and periodic reactivation.
We have performed several studies with a recombinant MDV, rMd5ΔMeq, constructed from a very virulent (vv) strain of MDV, Md5 by deleting both copies of meq gene. The rMd5ΔMeq lacks the ability to induce tumors and replicates for only up to two weeks in chickens. In spite of limited replication, rMd5ΔMeq elicited high levels of immune protection in chickens challenged continuously by exposure, suggesting that the rapid induction of specific innate immune signaling is sufficient to pattern the development of protective immune responses. Based on our observations and the ability of MDV to induce cytolytic infections in macrophages, we hypothesized that vaccine strains and pathogenic strains are sensed differently or pathogenic strains have developed mechanisms to modulate innate sensing by macrophages.
Subsequently, we developed a qPCR-chicken immune array (a panel of primers) targeting innate sensing and T-cell patterning pathways to delineate the differences in the innate sensing and polarization of adaptive immune system by MD vaccine and pathogenic strains. We tested our qPCR panel in an industry-funded trial studying the effects of an immune adjuvant on the efficacy of a recombinant MD vaccine, Vaxxitek HVT-IBD (Merial, Inc.) when co-administered. The immune adjuvant used was a cationic liposome-based non-coding plasmid DNA produced in E.coli (Victrio ® , Bayer Animal Health). In this study, the immune adjuvant did not show any adverse effects on MD vaccine protection and increased seroconversion of chickens to IBD. Gene expression analysis indicated that acceleration of innate immune responses, predominantly through interferon-response genes, was the likely mechanism of action of the immune adjuvant.
In a subsequent study, we applied a qPCR-based array to early rMd5ΔMeq-based signaling. Gene expression analysis suggested that pathogenic strains have developed mechanisms to modulate the innate sensing of macrophages, infiltration of dendritic cells and preferentially induce production of IL-23 and IL-12p80 with tumorigenic and immunosuppressive functions, respectively, rather than IL-12p70 with its TH1-polarizaiton and anti-tumor functions.
We have also tested the ability of rMd5ΔMeq to induce anti-tumor responses. In this study, rMd5ΔMeq did not induce anti-tumor immunity when administered after two weeks post-challenge, suggesting that either MD vaccine protection is comprised primarily of anti-virus responses or that rMd5ΔMeq elicits protection only in immune-competent chickens.