title: Autophagy restricts Chlamydia trachomatis growth in human macrophages via IFNG-inducible guanylate binding proteins.
abstract: Interferon γ (IFNG) is a key host response regulator of intracellular pathogen replication, including that of Chlamydia spp The antichlamydial functions of IFNG manifest in a strictly host, cell-type and chlamydial strain dependent manner. It has been recently shown that the IFNG-inducible family of immunity-related GTPases (IRG) proteins plays a key role in the defense against nonhost adapted chlamydia strains in murine epithelial cells. In humans, IFN-inducible guanylate binding proteins (hGBPs) have been shown to potentiate the antichlamydial effect of IFNG; however, how hGBPs regulate this property of IFNG is unknown. In this study, we identified hGBP1/2 as important resistance factors against C. trachomatis infection in IFNG-stimulated human macrophages. Exogenous IFNG reduced chlamydial infectivity by 50 percent in wild-type cells, whereas shRNA hGBP1/2 knockdown macrophages fully supported chlamydial growth in the presence of exogenous IFNG. hGBP1/2 were recruited to bacterial inclusions in human macrophages upon stimulation with IFNG, which triggered rerouting of the typically nonfusogenic bacterial inclusions for lysosomal degradation. Inhibition of lysosomal activity and autophagy impaired the IFNG-mediated elimination of inclusions. Thus, hGBP1/2 are critical effectors of antichlamydial IFNG responses in human macrophages. Through their capacity to remodel classically nonfusogenic chlamydial inclusions and stimulate fusion with autophagosomes, hGBP1/2 disable a major chlamydial virulence mechanism and contribute to IFNG-mediated pathogen clearance.
authors.affiliation: Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Munir A
authors.initials: MA
authors.lastname: Al-Zeer
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Al-Younes
authors.forename: Daniel
authors.initials: D
authors.lastname: Lauster
authors.forename: Mohammad
authors.initials: M
authors.lastname: Abu Lubad
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Meyer
mesh_terms: D001343:Autophagy / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D000071192:Autophagy-Related Protein 12; D002450:Cell Communication / Q000276:immunology; D002460:Cell Line; D002692:Chlamydia trachomatis / Q000254:growth & development* / Q000276:immunology / Q000472:pathogenicity*; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D002479:Inclusion Bodies / Q000187:drug effects / Q000276:immunology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D014774:Virulence / Q000235:genetics / Q000276:immunology
chemical_list: C466624:ATG12 protein, human; D000071192:Autophagy-Related Protein 12; C490287:GBP1 protein, human; C573415:IFNG protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D007371:Interferon-gamma; C534329:GBP2 protein, human; D019204:GTP-Binding Proteins