Listeria monocytogenes induces an interferon-enhanced activation of the integrated stress response that is detrimental for resolution of infection in mice

Eur J Immunol. 2017 May;47(5):830-840. doi: 10.1002/eji.201646856. Epub 2017 Apr 13.

Abstract

Type I interferons (IFNs) induce a detrimental response during Listeria monocytogenes (L. monocytogenes) infection. We were interested in identifying mechanisms linking IFN signaling to negative host responses against L. monocytogenes infection. Herein, we found that infection of myeloid cells with L. monocytogenes led to a coordinated induction of type I IFNs and activation of the integrated stress response (ISR). Infected cells did not induce Xbp1 splicing or BiP upregulation, indicating that the unfolded protein response was not triggered. CHOP (Ddit3) gene expression was upregulated during the ISR activation induced by L. monocytogenes. Myeloid cells deficient in either type I IFN signaling or PKR activation had less upregulation of CHOP following infection. CHOP-deficient mice showed lower expression of innate immune cytokines and were more resistant than wild-type counterparts following L. monocytogenes infection. These findings indicate that L. monocytogenes infection induces type I IFNs, which activate the ISR through PKR, which contributes to a detrimental outcome in the infected host.

Keywords: CHOP; Integrated stress response; Listeria; Listeriolysin O; Mouse; Type I interferon.

MeSH terms

  • Animals
  • Bacterial Toxins / genetics
  • Bacterial Toxins / immunology
  • Cytokines / biosynthesis
  • Cytokines / immunology
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / immunology
  • Heat-Shock Proteins / metabolism
  • Hemolysin Proteins / genetics
  • Hemolysin Proteins / immunology
  • Host-Pathogen Interactions*
  • Interferon Type I / biosynthesis
  • Interferon Type I / immunology*
  • Interferon Type I / metabolism*
  • Listeria monocytogenes / immunology*
  • Listeriosis / immunology*
  • Listeriosis / microbiology
  • Listeriosis / physiopathology
  • Mice
  • Myeloid Cells / immunology*
  • Myeloid Cells / microbiology
  • Transcription Factor CHOP / deficiency
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism
  • X-Box Binding Protein 1 / genetics
  • X-Box Binding Protein 1 / metabolism
  • eIF-2 Kinase / metabolism

Substances

  • Bacterial Toxins
  • Cytokines
  • Ddit3 protein, mouse
  • Heat-Shock Proteins
  • Hemolysin Proteins
  • Interferon Type I
  • X-Box Binding Protein 1
  • Xbp1 protein, mouse
  • Transcription Factor CHOP
  • eIF-2 Kinase
  • protein kinase R, mouse
  • hlyA protein, Listeria monocytogenes
  • molecular chaperone GRP78