Constitutive Interferon Maintains GBP Expression Required for Release of Bacterial Components Upstream of Pyroptosis and Anti-DNA Responses.

Abstract

Legionella pneumophila elicits caspase-11-driven macrophage pyroptosis through guanylate-binding proteins (GBPs) encoded on chromosome 3. It has been proposed that microbe-driven IFN upregulates GBPs to facilitate pathogen vacuole rupture and bacteriolysis preceding caspase-11 activation. We show here that macrophage death occurred independently of microbial-induced IFN signaling and that GBPs are dispensable for pathogen vacuole rupture. Instead, the host-intrinsic IFN status sustained sufficient GBP expression levels to drive caspase-1 and caspase-11 activation in response to cytosol-exposed bacteria. In addition, endogenous GBP levels were sufficient for the release of DNA from cytosol-exposed bacteria, preceding the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway for Ifnb induction. Mice deficient for chromosome 3 GBPs were unable to mount a rapid IL-1/chemokine (C-X-C motif) ligand 1 (CXCL1) response during Legionella-induced pneumonia, with defective bacterial clearance. Our results show that rapid GBP activity is controlled by host-intrinsic cytokine signaling and that GBP activities precede immune amplification responses, including IFN induction, inflammasome activation, and cell death.

• Authors: Beiyun C Liu, Joseph Sarhan, Alexander Panda, Hayley I Muendlein, Vladimir Ilyukha, Jörn Coers, Masahiro Yamamoto, Ralph R Isberg, Alexander Poltorak
• Journal: Cell reports (Cell Rep) Vol. 24 Issue 1 Pg. 155-168.e5 (07 03 2018) ISSN: 2211-1247 [Electronic] United States
• PMID: 29972777 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Anti-Infective Agents
• DNA, Bacterial
• STAT Transcription Factors
• Receptor, Interferon alpha-beta
• Interferons
• Janus Kinases
• GTP-Binding Proteins

Topics

• Animals
• Anti-Infective Agents (pharmacology)
• Chromosomes, Mammalian (metabolism)
• Cytosol (metabolism)
• DNA, Bacterial (metabolism)
• Female
• GTP-Binding Proteins (metabolism)
• Humans
• Interferons (metabolism)
• Janus Kinases (metabolism)
• Legionella (metabolism)
• Legionellosis (microbiology)
• Macrophages (cytology)
• Male
• Mice, Inbred C57BL
• Pneumonia (microbiology, pathology)
• Pyroptosis
• Receptor, Interferon alpha-beta (metabolism)
• STAT Transcription Factors (metabolism)
• Signal Transduction
• Vacuoles (metabolism)