title: Guanylate binding proteins enable rapid activation of canonical and noncanonical inflammasomes in Chlamydia-infected macrophages.
abstract: Interferon (IFN)-inducible guanylate binding proteins (GBPs) mediate cell-autonomous host resistance to bacterial pathogens and promote inflammasome activation. The prevailing model postulates that these two GBP-controlled activities are directly linked through GBP-dependent vacuolar lysis. It was proposed that the rupture of pathogen-containing vacuoles (PVs) by GBPs destroyed the microbial refuge and simultaneously contaminated the host cell cytosol with microbial activators of inflammasomes. Here, we demonstrate that GBP-mediated host resistance and GBP-mediated inflammatory responses can be uncoupled. We show that PVs formed by the rodent pathogen Chlamydia muridarum, so-called inclusions, remain free of GBPs and that C. muridarum is impervious to GBP-mediated restrictions on bacterial growth. Although GBPs neither bind to C. muridarum inclusions nor restrict C. muridarum growth, we find that GBPs promote inflammasome activation in C. muridarum-infected macrophages. We demonstrate that C. muridarum infections induce GBP-dependent pyroptosis through both caspase-11-dependent noncanonical and caspase-1-dependent canonical inflammasomes. Among canonical inflammasomes, we find that C. muridarum and the human pathogen Chlamydia trachomatis activate not only NLRP3 but also AIM2. Our data show that GBPs support fast-kinetics processing and secretion of interleukin-1β (IL-1β) and IL-18 by the NLRP3 inflammasome but are dispensable for the secretion of the same cytokines at later times postinfection. Because IFN-γ fails to induce IL-1β transcription, GBP-dependent fast-kinetics inflammasome activation can drive the preferential processing of constitutively expressed IL-18 in IFN-γ-primed macrophages in the absence of prior Toll-like receptor stimulation. Together, our results reveal that GBPs control the kinetics of inflammasome activation and thereby shape macrophage responses to Chlamydia infections.
authors.affiliation: Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Finethy
authors.affiliation: Department of Microbiology and Immunology and Lineberger Comprehensive Cancer Center, and Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Ine
authors.initials: I
authors.lastname: Jorgensen
authors.affiliation: Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Haldar
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Marcel R
authors.initials: MR
authors.lastname: de Zoete
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA Helmholtz Center for Infection Research, Braunschweig, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Strowig
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: Department of Immunoparasitology, Research Institute for Microbial Diseases, Laboratory of Immunoparasitology, WPI Immunology Frontier Research Center, Osaka University, Yamadaoka, Suita, Osaka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Uma M
authors.initials: UM
authors.lastname: Nagarajan
authors.affiliation: Department of Microbiology and Immunology and Lineberger Comprehensive Cancer Center, and Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, North Carolina, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Miao
authors.affiliation: Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, North Carolina, USA jorn.coers@duke.edu.
authors.forename: Jörn
authors.initials: J
authors.lastname: Coers
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D020169:Caspases / Q000235:genetics / Q000276:immunology; D053471:Caspases, Initiator; D002690:Chlamydia Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D023502:Chlamydia muridarum / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D002692:Chlamydia trachomatis / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D005347:Fibroblasts / Q000276:immunology / Q000382:microbiology; D019204:GTP-Binding Proteins / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D002479:Inclusion Bodies / Q000276:immunology / Q000382:microbiology; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D061251:Primary Cell Culture; D015398:Signal Transduction; D014617:Vacuoles / Q000276:immunology / Q000382:microbiology
chemical_list: C410167:AIM2 protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C490288:Gbp2b protein, mouse; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D007371:Interferon-gamma; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D019204:GTP-Binding Proteins; C452200:Gbp2 protein, mouse