title: Human metapneumovirus small hydrophobic (SH) protein downregulates type I IFN pathway signaling by affecting STAT1 expression and phosphorylation.
abstract: Type I interferon (IFN) is a key mediator of antiviral immunity. Human metapneumovirus (HMPV) inhibits IFN signaling, but does not encode homologues of known IFN antagonists. We tested the hypothesis that a specific viral protein prevents type I IFN signaling by targeting signal transducer and activator of transcription-1 (STAT1). We found that human airway epithelial cells (capable of expressing IFNs) became impaired for STAT1 phosphorylation even without direct infection due to intrinsic negative feedback. HMPV-infected Vero cells (incapable of expressing IFN) displayed lower STAT1 expression and impaired STAT1 phosphorylation in response to type I IFN treatment compared to mock-infected cells. Transient overexpression of HMPV small hydrophobic (SH) protein significantly inhibited STAT1 phosphorylation and signaling, and recombinant virus lacking SH protein was unable to inhibit STAT1 phosphorylation. Our results indicate a role for the SH protein of HMPV in the downregulation of type I IFN signaling through the targeting of STAT1.
authors.affiliation: Department of Pathology, Microbiology & Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Hastings
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Amato
authors.affiliation: Department of Pathology, Microbiology & Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States.
authors.forename: Sherry C
authors.initials: SC
authors.lastname: Wen
authors.affiliation: Department of Pathology, Microbiology & Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Peterson
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, United States. Electronic address: jvw@chp.edu.
authors.forename: John V
authors.initials: JV
authors.lastname: Williams
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D029121:Metapneumovirus / Q000502:physiology*; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D014709:Vero Cells; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D007370:Interferon Type I; D050794:STAT1 Transcription Factor; D014764:Viral Proteins
keywords: Interferon; Metapneumovirus; Paramyxovirus; Small hydrophobic protein