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Constitutive Interferon Maintains GBP Expression Required for Release of Bacterial Components Upstream of Pyroptosis

Beiyun C Liu1, Joseph Sarhan2, Alexander Panda3

  • 1Graduate Program in Immunology, Tufts University Sackler School of Biomedical Sciences, Boston, MA 02111, USA.

Cell Reports
|July 5, 2018
PubMed

Insights

Host guanylate-binding proteins (GBPs) drive Legionella-induced pyroptosis independently of microbial signals. Host cytokine signaling controls GBP activity, which precedes immune amplification and cell death.

Area of Science:

  • Innate immunity
  • Cellular microbiology
  • Host-pathogen interactions

Background:

  • Legionella pneumophila induces macrophage pyroptosis via caspase-11, involving guanylate-binding proteins (GBPs).
  • Previous models proposed microbial IFN signaling upregulates GBPs to promote bacterial vacuole rupture and lysis before caspase-11 activation.

Purpose of the Study:

  • To investigate the role of host-intrinsic IFN signaling in GBP-mediated pyroptosis during Legionella infection.
  • To determine if GBPs are required for pathogen vacuole rupture and to clarify the temporal relationship between GBP activity and immune signaling pathways.

Main Methods:

  • Macrophage cell culture and infection models.
  • Analysis of host gene expression (IFN, GBPs) and signaling pathways (caspase-1, caspase-11, cGAS/STING).
  • Murine models of Legionella-induced pneumonia with wild-type and GBP-deficient mice.

Main Results:

  • Macrophage death occurred independently of microbial-induced IFN signaling.
  • GBPs were dispensable for pathogen vacuole rupture but essential for caspase-1 and caspase-11 activation.
  • Endogenous GBP levels facilitated DNA release from bacteria, preceding cGAS/STING pathway activation and IFN-beta induction.
  • Mice lacking chromosome 3 GBPs showed impaired IL-1/CXCL1 responses and defective bacterial clearance during Legionella pneumonia.

Conclusions:

  • Host-intrinsic cytokine signaling, not microbial IFN, controls rapid GBP activity.
  • GBP activity precedes key immune amplification events like IFN induction, inflammasome activation, and pyroptosis.
  • GBPs are critical for early host defense against Legionella by enabling bacterial DNA release and subsequent immune responses.
Keywords:
AIM2GBPscGAS/STINGcaspase-11cytosolic sensingguanylate-binding proteinslegionellapyroptosistonic/constitutive interferon

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