Location: Endemic Poultry Viral Diseases Research
Project Number: 6040-32000-083-006-A
Project Type: Cooperative Agreement
Start Date: Jul 1, 2020
End Date: May 30, 2023
Objective:
Marek’s disease (MD), is a highly contagious lymphoproliferative disease caused by Marek’s disease virus (MDV), an alphaherpesvirus. MD is a major economic threat to farmed poultry. Currently, MD is controlled by universal vaccination with a live attenuated virus strain called “CVI988. Although this strain provides sufficient protection against nearly all field isolates, recent history tells us that with time new virulent strains will evolve, emerge, and break the current protection. Herein we propose to develop new live attenuated vaccine strains for MD. First, we will identify heretofore-unknown virulence factors which inhibit the production of the type I interferons (IFNs), using homology to existing virulence factors in similar alphaherpesviruses. Second, we will use this new information to rationally design recombinant mutants of MDV which are compromised for their ability to inhibit the production of virulence factors which inhibit the production of type I IFNs. Infection with these potential vaccine strains will result in the production of greater amounts of type I IFNs, which will in turn improve their immunogenicity and improve their vaccinal protection. Our Cooperator is an expert in the assembly of large genomes and we will rely upon them for randomly mutated genes to identify functionally relevant portions of the virulence factors we discover, and to synthesize whole MDV viral genomes (BACs) for in vitro and in vivo testing. If successful, this project will result in new and more protective vaccine strains for MDV, suitable for commercial use.
Approach:
Using our in vitro model that simulates herpesvirus infection and quantifies the type I IFNs produced as our assay, we will identify the virulence factors encoded by Marek’s disease virus (MDV) that suppress the production of IFN. Furthermore, we will use this information to engineer MDV recombinants ablated for these factors and test them for vaccinal protection. We hypothesize that the recombinant strains produced will be less able to inhibit the production of IFNa and IFNb, which in turn will result in higher amounts of these cytokines being produced in infected cells and make more type I IFNs available to simultaneously attenuate the virus and improve its immunogenicity and suitability as a live attenuated vaccine (LAV).
We are attempting to approach useful LAV vaccine strains from two conceptual directions, to increase our probability of success. We will use two “backbone” MDV strains, one strain at each extreme on the spectrum of virulence. We propose to both improve an existing vaccine strain of MDV that is no longer used as a vaccine strain because it was insufficiently protective (i.e., MDV 301B/1) and, simultaneously, attenuate a strain not currently used as a LAV because it is highly virulent (i.e., MDV Md5). In this we are attempting to achieve the “delicate balance” between LAV virulence and protection.
