Grant: Discovery Grants Program - Individual

Herpesviruses are composed of four concentric compartments, the nucleoprotein core surrounding the DNA, the capsid, the tegument and the envelope. The tegument contains at least 15 proteins, which play an important role in viral infection, because they are the first to interact with the intracellular environment and at a later stage they associate to create new virions. The long-term objective of this program is to perform a functional characterization of the tegument proteins of bovine herpesvirus-1 (BHV-1), one of the major pathogens in bovine respiratory disease. The specific objective of this proposal is to further characterize the functions of VP8, which is the major tegument protein in BHV-1. Additional tegument proteins, in particular those that interact with VP8 will be studied following similar approaches. A mutant virus lacking VP8 was impaired in vitro and non-virulent in vivo, which suggests that in addition to a structural role VP8 has an important early function, possibly modulating innate immune responses. Our hypothesis is that VP8 plays a role both in establishing conditions for efficient viral replication and in promoting virus assembly. We will test this as follows: i) Since VP8 has RNA binding activity, we will examine the early effects of VP8 on viral mRNA transport; ii) Interestingly, VP8 interacts with DNA damage-binding protein-1 and culllin4A, so we will determine whether VP8 hijacks the cullin-4A-DDB1 E3 ubiquitin ligase to control protein degradation in infected cells, and possibly block interferon signaling; iii) In the absence of VP8 we observed reduced numbers of mature virions, so we will assess the role of VP8 in virus assembly; iv) As VP8 is phosphorylated, we will define the impact of VP8 phosphorylation on its functional properties. By characterizing tegument proteins of BHV-1, we will gain insight into the replication and morphogenesis of a complex virus, which will have implications for prevention and control of herpesvirus infections. The availability of cattle as the natural host for in vivo testing provides an advantage for the development of vaccines and therapeutics, not only for BHV-1 but also for related herpesviruses, which will benefit human health as well as the livestock industry in Canada.