The cGas-Sting Signaling Pathway Is Required for the Innate Immune Response Against Ectromelia Virus

Front Immunol. 2018 Jun 14;9:1297. doi: 10.3389/fimmu.2018.01297. eCollection 2018.

Abstract

Activation of the DNA-dependent innate immune pathway plays a pivotal role in the host defense against poxvirus. Cyclic GMP-AMP synthase (cGAS) is a key cytosolic DNA sensor that produces the cyclic dinucleotide cGMP-AMP (cGAMP) upon activation, which triggers stimulator of interferon genes (STING), leading to type I Interferons (IFNs) production and an antiviral response. Ectromelia virus (ECTV) has emerged as a valuable model for investigating the host-Orthopoxvirus relationship. However, the role of cGas-Sting pathway in response to ECTV is not clearly understood. Here, we showed that murine cells (L929 and RAW264.7) mount type I IFN responses to ECTV that are dependent upon cGas, Sting, TANK binding kinase 1 (Tbk1), and interferon regulatory factor 3 (Irf3) signaling. Disruption of cGas or Sting expression in mouse macrophages blocked the type I IFN production and facilitated ECTV replication. Consistently, mice deficient in cGas or Sting exhibited lower type I IFN levels and higher viral loads, and are more susceptible to mousepox. Collectively, our study indicates that the cGas-Sting pathway is critical for sensing of ECTV infection, inducing the type I IFN production, and controlling ECTV replication.

Keywords: Sting; cGas; ectromelia virus; innate immunity; type I interferon.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chlorocebus aethiops
  • Ectromelia virus / immunology*
  • Ectromelia, Infectious / immunology*
  • Ectromelia, Infectious / metabolism*
  • Ectromelia, Infectious / virology
  • Host-Pathogen Interactions
  • Humans
  • Immunity, Innate*
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Type I / biosynthesis
  • Macrophages / immunology
  • Macrophages / metabolism
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • NIH 3T3 Cells
  • Nucleotidyltransferases / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • RAW 264.7 Cells
  • Signal Transduction*
  • Vero Cells
  • Virus Replication

Substances

  • Interferon Regulatory Factor-3
  • Interferon Type I
  • Membrane Proteins
  • Sting1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Nucleotidyltransferases
  • cGAS protein, mouse