title: Interferon Regulatory Factor 1 and Type I Interferon Cooperate To Control Acute Gammaherpesvirus Infection.
abstract: Gammaherpesviruses are ubiquitous pathogens that establish lifelong infection in >95% of adults worldwide and are associated with a variety of malignancies. Coevolution of gammaherpesviruses with their hosts has resulted in an intricate relationship between the virus and the host immune system, and perturbation of the virus-host balance results in pathology. Interferon regulatory factor 1 (IRF-1) is a tumor suppressor that is also involved in the regulation of innate and adaptive immune responses. Here, we show that type I interferon (IFN) and IRF-1 cooperate to control acute gammaherpesvirus infection. Specifically, we demonstrate that a combination of IRF-1 and type I IFN signaling ensures host survival during acute gammaherpesvirus infection and supports IFN gamma-mediated suppression of viral replication. Thus, our studies reveal an intriguing cross talk between IRF-1 and type I and II IFNs in the induction of the antiviral state during acute gammaherpesvirus infection.
  
  
  OBJECTIVE
  Gammaherpesviruses establish chronic infection in a majority of adults, and this long-term infection is associated with virus-driven development of a range of malignancies. In contrast, a brief period of active gammaherpesvirus replication during acute infection of a naive host is subclinical in most individuals. Here, we discovered that a combination of type I interferon (IFN) signaling and interferon regulatory factor 1 (IRF-1) expression is required to ensure survival of a gammaherpesvirus-infected host past the first 8 days of infection. Specifically, both type I IFN receptor and IRF-1 expression potentiated antiviral effects of type II IFN to restrict gammaherpesvirus replication in vivo, in the lungs, and in vitro, in primary macrophage cultures.
authors: Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors: Wadzanai P
authors: WP
authors: Mboko
authors: Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors: Michaela M
authors: MM
authors: Rekow
authors: Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors: Mitchell P
authors: MP
authors: Ledwith
authors: Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors: Philip T
authors: PT
authors: Lange
authors: Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors: Kaitlin E
authors: KE
authors: Schmitz
authors: Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors: Sean
authors: S
authors: Anderson
authors: Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA vera@mcw.edu.|Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors: Vera L
authors: VL
authors: Tarakanova
mesh_terms: D000818:Animals; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000276:immunology; D034961:Antigens, Nuclear / Q000235:genetics / Q000276:immunology; D018142:Gammaherpesvirinae / Q000254:growth & development / Q000472:pathogenicity*; D005786:Gene Expression Regulation; D006566:Herpesviridae Infections / Q000235:genetics / Q000276:immunology* / Q000401:mortality / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000235:genetics* / Q000276:immunology; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000276:immunology; D000072640:Interferon-Induced Helicase, IFIH1 / Q000235:genetics / Q000276:immunology; D016898:Interferon-alpha / Q000235:genetics* / Q000276:immunology; D016899:Interferon-beta / Q000235:genetics* / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000821:virology; D008264:Macrophages / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061251:Primary Cell Culture; D011506:Proteins / Q000235:genetics / Q000276:immunology; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000821:virology; D016019:Survival Analysis; D000090123:Viperin Protein
chemical_list: D015214:Antigens, Differentiation, Myelomonocytic; D034961:Antigens, Nuclear; D050856:Interferon Regulatory Factor-1; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D000072640:Interferon-Induced Helicase, IFIH1; D016898:Interferon-alpha; D016899:Interferon-beta; D007371:Interferon-gamma; D011506:Proteins; D053633:Receptor, Interferon alpha-beta; C508032:Ifnar1 protein, mouse; C581198:Mnda protein, mouse; C417529:Rsad2 protein, mouse; D000090123:Viperin Protein; C510592:Ifih1 protein, mouse
keywords: IRF-1; acute infection; gammaherpesvirus; interferon; viral replication