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 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-beta)-induced antiviral state in primary rat fibroblasts. Using microarray technology, we found that the expression of a subset of genes normally induced by IFN-beta 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-beta response offers an explanation for the uniform lethality of virulent PRV infection of nonnatural hosts.
Brukman
Alla
A
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Enquist
L W
LW
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology; D000998:Antiviral Agents / Q000276:immunology* / Q000494:pharmacology; D002460:Cell Line; D002644:Chickenpox / Q000188:drug therapy / Q000276:immunology; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D005805:Genes, MHC Class I / Q000276:immunology; D006561:Herpes Simplex / Q000188:drug therapy / Q000276:immunology; D018259:Herpesvirus 1, Human / Q000276:immunology; D011558:Herpesvirus 1, Suid / Q000276:immunology*; D014645:Herpesvirus 3, Human / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D016899:Interferon-beta / Q000276:immunology* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D011557:Pseudorabies / Q000188:drug therapy / Q000276:immunology*; D051381:Rats; D050794:STAT1 Transcription Factor / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013552:Swine
D000998:Antiviral Agents; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D016899:Interferon-beta