Pseudorabies virus (PRV) is an alphaherpesvirus related to the human pathogens herpes simplex virus type 1 (HSV-1) and varicella-zoster virus. PRV is capable of infecting and killing a wide variety of mammals. How it avoids innate immune defenses in so many hosts is not understood. While the anti-interferon (IFN) strategies of HSV-1 have been studied, little is known about how PRV evades the IFN-mediated immune response. In this study, we determined if wild-type PRV infection can overcome the establishment of a beta interferon (IFN-)-induced antiviral state in primary rat fibroblasts. Using microarray technology, we found that the expression of a subset of genes normally induced by IFN- in these cells was not induced when the cells were simultaneously infected with a wild-type PRV strain. Expression of transcripts associated with major histocompatibility complex 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 phosphorylation of STAT1, became less effective in PRV-infected cells. At least one virion-associated protein is involved in inhibition of STAT1 tyrosine phosphorylation. This ability to disarm the IFN- response offers an explanation for the uniform lethality of virulent PRV infection of nonnatural hosts.Pseudorabies virus (PRV) is a swine alphaherpesvirus related to the human pathogens herpes simplex virus type 1 (HSV-1) and HSV-2 and varicella-zoster virus (30). PRV has a broad host range, infecting most mammals except higher-order primates. Wild-type PRV infection causes primarily respiratory and reproductive disease with low mortality in its natural host, the adult pig. Infection of nonnatural hosts leads to neurological symptoms and is invariably fatal. Two explanations for the high mortality of nonnatural hosts have been proposed: either the immune system fails to control the infection and viral replication destroys cells and tissues or the immune system responds too strongly and a systemic inflammatory response overwhelms the host (2). The interferon (IFN)-mediated innate immune system is the front line of host defense against viral infections (34,35). The IFNs are a family of secreted cytokines involved in establishing an antiviral state in cells. Type I (alpha and beta) IFNs (IFN-␣ and IFN-) are produced by cells as a direct response to viral infection. After secretion, type I IFN binds to its cognate receptor on the cell surface, and in response to this binding, JAK1 and TYK2 kinases associated with the cytoplasmic portion of the receptor become activated and phosphorylated. The activated kinases, in turn, phosphorylate signal transducer and activator of transcription 1 (STAT1) and STAT2 transcription factors. Phosphorylated STATs form a complex and translocate to the nucleus, where they induce the transcription of genes containing IFN response elements in their u...
Pseudorabies virus (PRV), an alphaherpesvirus related to herpes simplex virus type 1 and varicella-zoster virus, infects a broad host range of mammals. A striking characteristic of PRV infection is the different symptoms and outcomes of infection in natural and nonnatural hosts. Adult pigs, the natural hosts of PRV, survive infection with only mild respiratory symptoms, while nonnatural hosts, including rodents and cattle, invariably die after exhibiting neurological symptoms. Here, we show that the PRV EP0 protein is necessary to overcome an interferon-mediated antiviral response in primary cells from the natural host of PRV but is not necessary in nonnatural-host cells.Pseudorabies virus (PRV) is a member of the alphaherpesvirus subfamily related to the human pathogens herpes simplex virus type 1 (HSV-1) and HSV-2 and varicella-zoster virus (17). Like many alphaherpesviruses, PRV infects a broad range of mammals, including rodents, cattle, dogs, and cats (15). Higher-order primates, including humans, are not susceptible to PRV infection. A striking characteristic of PRV infection is the different symptoms and outcomes of infection in natural and nonnatural hosts. Wild-type PRV infection causes respiratory and reproductive disease in its natural host, the adult pig, and mortality is rare (15). In contrast, nonnatural hosts infected with PRV exhibit neurological symptoms and die as a result of infection. The death of nonnatural hosts may be caused by a systemic inflammatory response (1). The type I interferon (IFN) system is the front line of host antiviral defense and is involved in establishing an inflammatory response (7,19). Accordingly, the different outcomes of PRV infection in natural and nonnatural hosts may be linked to how PRV infection engages the IFN system in natural and nonnatural hosts.The HSV-1 protein ICP0 prevents the transcriptional induction of IFN-stimulated genes (4). ICP0-null mutants are sensitive to IFN-␣ pretreatment in a cell line-specific manner (11). While PRV EP0 is considered a homolog of ICP0 because of its position in the genome and its function as a transcriptional activator, the two genes exhibit different temporal expression and have low sequence similarity outside their N-terminal domains (14,15). In this report, we compared the growth of PRV EP0 deletion mutants with that of HSV-1 ICP0 deletion mutants in the presence and absence of IFN. We wanted to determine whether the growth levels of these two mutants were equally sensitive to IFN pretreatment in primary fibroblasts from natural and nonnatural hosts.Monolayers of primary fibroblasts from natural and nonnatural hosts of PRV were treated with 1,000 U/ml of the species-appropriate IFN-␣ (PBL Biomedical Laboratories) and infected 24 h later with either PRV Be or the PRV EP0 deletion mutant (PRV EP0-1) (2) at 1 PFU per cell. The natural host cells of PRV were pig embryonic lung fibroblasts (PELF) and pig embryonic spleen fibroblasts (C. Jones, University of Nebraska). Nonnatural host cells for PRV were rat embryonic fibrobla...
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