title: Helminth infection reactivates latent γ-herpesvirus via cytokine competition at a viral promoter.
abstract: Mammals are coinfected by multiple pathogens that interact through unknown mechanisms. We found that helminth infection, characterized by the induction of the cytokine interleukin-4 (IL-4) and the activation of the transcription factor Stat6, reactivated murine γ-herpesvirus infection in vivo. IL-4 promoted viral replication and blocked the antiviral effects of interferon-γ (IFNγ) by inducing Stat6 binding to the promoter for an important viral transcriptional transactivator. IL-4 also reactivated human Kaposi's sarcoma-associated herpesvirus from latency in cultured cells. Exogenous IL-4 plus blockade of IFNγ reactivated latent murine γ-herpesvirus infection in vivo, suggesting a "two-signal" model for viral reactivation. Thus, chronic herpesvirus infection, a component of the mammalian virome, is regulated by the counterpoised actions of multiple cytokines on viral promoters that have evolved to sense host immune status.
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: T A
authors: TA
authors: Reese
authors: Emory University Vaccine Center, Atlanta, GA 30322, USA.
authors: B S
authors: BS
authors: Wakeman
authors: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
authors: H S
authors: HS
authors: Choi
authors: Departments of Pediatrics and Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors: M M
authors: MM
authors: Hufford
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: S C
authors: SC
authors: Huang
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: X
authors: X
authors: Zhang
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: M D
authors: MD
authors: Buck
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: A
authors: A
authors: Jezewski
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: A
authors: A
authors: Kambal
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: C Y
authors: CY
authors: Liu
authors: Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors: G
authors: G
authors: Goel
authors: Departments of Infectious Diseases and Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors: P J
authors: PJ
authors: Murray
authors: Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors: R J
authors: RJ
authors: Xavier
authors: Departments of Pediatrics and Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors: M H
authors: MH
authors: Kaplan
authors: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610, USA.
authors: R
authors: R
authors: Renne
authors: Emory University Vaccine Center, Atlanta, GA 30322, USA.
authors: S H
authors: SH
authors: Speck
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: M N
authors: MN
authors: Artyomov
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: E J
authors: EJ
authors: Pearce
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. virgin@wustl.edu.
authors: H W
authors: HW
authors: Virgin
mesh_terms: D000818:Animals; D018142:Gammaherpesvirinae / Q000235:genetics / Q000502:physiology*; D015967:Gene Expression Regulation, Viral; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology* / Q000494:pharmacology; D015847:Interleukin-4 / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009351:Nematospiroides dubius / Q000276:immunology; D010063:Ovum / Q000276:immunology; D011401:Promoter Regions, Genetic; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D012550:Schistosoma mansoni / Q000276:immunology*; D012555:Schistosomiasis mansoni / Q000276:immunology*; D017206:Strongylida Infections / Q000276:immunology; D014775:Virus Activation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D017735:Virus Latency / Q000502:physiology; D014779:Virus Replication / Q000502:physiology
chemical_list: D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4; D007371:Interferon-gamma