期刊
CELL REPORTS
卷 24, 期 1, 页码 155-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2018.06.012
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资金
- NIH [AI126050, AI135369]
- Russian Science Fund [15-15-00100]
- HHMI [R01AI-113211]
- NIAID [R01AI-113211]
- HHMI MERGE-ID initiative [56006767]
- NIAID training grant [T32 AI 007077]
- [6.5111.2017/BCH]
- Russian Science Foundation [18-15-16000, 15-15-00100] Funding Source: Russian Science Foundation
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. Inaddition, endogenousGBPlevels 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.
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