Respiratory syncytial virus NS1 inhibits anti-viral Interferon-α-induced JAK/STAT signaling, by limiting the nuclear translocation of STAT1.

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  • Additional Information
    • Source:
      Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE
    • Publication Information:
      Original Publication: [Lausanne : Frontiers Research Foundation]
    • Subject Terms:
      STAT1 Transcription Factor*/metabolism ; Signal Transduction* ; Interferon-alpha*/metabolism ; Interferon-alpha*/pharmacology ; Interferon-alpha*/immunology ; Respiratory Syncytial Virus, Human*/immunology ; Respiratory Syncytial Virus, Human*/physiology ; Viral Nonstructural Proteins*/metabolism ; Respiratory Syncytial Virus Infections*/immunology ; Respiratory Syncytial Virus Infections*/metabolism ; Respiratory Syncytial Virus Infections*/virology; Humans ; Janus Kinases/metabolism ; Cell Nucleus/metabolism ; Phosphorylation ; Active Transport, Cell Nucleus ; Cell Line
    • Abstract:
      Human respiratory viruses are the most prevalent cause of disease in humans, with the highly infectious RSV being the leading cause of infant bronchiolitis and viral pneumonia. Responses to type I IFNs are the primary defense against viral infection. However, RSV proteins have been shown to antagonize type I IFN-mediated antiviral innate immunity, specifically dampening intracellular IFN signaling. Respiratory epithelial cells are the main target for RSV infection. In this study, we found RSV-NS1 interfered with the IFN-α JAK/STAT signaling pathway of epithelial cells. RSV-NS1 expression significantly enhanced IFN-α-mediated phosphorylation of STAT1, but not pSTAT2; and neither STAT1 nor STAT2 total protein levels were affected by RSV-NS1. However, expression of RSV-NS1 significantly reduced ISRE and GAS promoter activity and anti-viral IRG expression. Further mechanistic studies demonstrated RSV-NS1 bound STAT1, with protein modeling indicating a possible interaction site between STAT1 and RSV-NS1. Nuclear translocation of STAT1 was reduced in the presence of RSV-NS1. Additionally, STAT1's interaction with the nuclear transport adapter protein, KPNA1, was also reduced, suggesting a mechanism by which RSV blocks STAT1 nuclear translocation. Indeed, reducing STAT1's access to the nucleus may explain RSV's suppression of IFN JAK/STAT promoter activation and antiviral gene induction. Taken together these results describe a novel mechanism by which RSV controls antiviral IFN-α JAK/STAT responses, which enhances our understanding of RSV's respiratory disease progression.
      Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
      (Copyright © 2024 Efstathiou, Zhang, Kandwal, Fayne, Molloy and Stevenson.)
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    • Contributed Indexing:
      Keywords: Interferon; JAK/STAT signaling; RSV; nuclear translocation; viral immune evasion
    • Accession Number:
      0 (STAT1 Transcription Factor)
      0 (Interferon-alpha)
      0 (STAT1 protein, human)
      0 (Viral Nonstructural Proteins)
      EC 2.7.10.2 (Janus Kinases)
    • Publication Date:
      Date Created: 20240628 Date Completed: 20240628 Latest Revision: 20240629
    • Publication Date:
      20240629
    • Accession Number:
      PMC11208467
    • Accession Number:
      10.3389/fimmu.2024.1395809
    • Accession Number:
      38938568