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

• Published in: Cell reports (Cambridge) 2018-07, Vol.24 (1), p.155-168.e5
• Main Authors: Liu, Beiyun C., Sarhan, Joseph, Panda, Alexander, Muendlein, Hayley I., Ilyukha, Vladimir, Coers, Jörn, Yamamoto, Masahiro, Isberg, Ralph R., Poltorak, Alexander
• Format: Article
• Language: English
• Subjects: AIM2; Animals; Anti-Infective Agents - pharmacology; caspase-11; cGAS/STING; Chromosomes, Mammalian - metabolism; Cytosol - metabolism; cytosolic sensing; DNA, Bacterial - metabolism; Female; GBPs; GTP-Binding Proteins - metabolism; guanylate-binding proteins; Humans; Interferons - metabolism; Janus Kinases - metabolism; legionella; Legionella - metabolism; Legionellosis - microbiology; Macrophages - cytology; Male; Mice, Inbred C57BL; Pneumonia - microbiology; Pneumonia - pathology; Pyroptosis; Receptor, Interferon alpha-beta - metabolism; Signal Transduction; STAT Transcription Factors - metabolism; tonic/constitutive interferon; Vacuoles - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.06.012

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. [Display omitted] •Infection-driven IFN is dispensable for pyroptosis against cytosolic Legionella•Constitutive IFN maintains GBP expression in murine and human macrophages•GBPs are needed to release bacterial content from cytosolic Legionella bacteria•GBPs are required for restriction of Legionella bacterial growth in vivo Guanylate-binding proteins act upstream of many cytosolic pathogen sensors. It is assumed that infection-associated IFN signaling precedes GBP induction. Liu et al. find that host-intrinsic IFN signaling maintains GBPs in naive macrophages to mediate the disruption of cytosol-accessible bacteria. The findings elucidate a crucial role of tonic cytokines in maintaining immune readiness.