Suppression of the interferon-mediated innate immune response by pseudorabies virus

Pseudorabies virus (PRV) is an alphaherpesvirus related to the human pathogens herpes simplex virus-1 (HSV-1) and varicella-zoster virus (VZV). PRV is capable of infecting and killing a wide variety of mammals. Wild-type PRV infection causes low mortality in its natural host, the adult pig, while infection of non-natural hosts such as rodents and cattle is invariably fatal. The questions of how PRV avoids innate immune defenses in so many hosts and why the outcomes of PRV infection are different in natural and non-natural hosts are well not understood. While the anti-IFN strategies of HSV-1 have been studied at length, little is known about how PRV evades the IFN-mediated immune response. In this thesis, I determined if wild-type PRV infection can overcome the establishment of an interferon (IFN) beta-induced antiviral state in primary rat fibroblasts. Using microarray technology, I found that the expression of a subset of genes normally induced by IFNbeta in these cells was not induced when the cells were simultaneously infected with a wild-type PRV strain. Expression of transcripts associated with MHC class I antigen presentation and NK cell activation was reduced while transcripts associated with inflammation either were unaffected or were induced by viral infection. This suppression of IFN-stimulated gene expression occurred because IFN signal transduction, in particular the tyrosine phosphorylation of STAT1, became less effective in PRV-infected cells. At least one virion-associated protein is involved in inhibition of STAT1 tyrosine phosphorylation.; The growth of an EP0 deletion mutant in IFNalpha pre-treated primary fibroblasts from natural and non-natural hosts of PRV was compared to the growth of PRV Be. The EP0 deletion mutant was more sensitive to IFNalpha pre-treatment in natural host cells than non-natural host cells. Because the EP0 protein was found to be associated with the PRV virion, it is available for use as soon as the virus enters a cell that has been placed in an antiviral state. PRV encodes two modes of anti-IFN countermeasures, and the fact that one of them functions only in natural host cells may explain the different symptoms and outcomes of infection in natural and non-natural hosts.