title: IFN-gamma-inducible Irga6 mediates host resistance against Chlamydia trachomatis via autophagy.
abstract: Chlamydial infection of the host cell induces Gamma interferon (IFNgamma), a central immunoprotector for humans and mice. The primary defense against Chlamydia infection in the mouse involves the IFNgamma-inducible family of IRG proteins; however, the precise mechanisms mediating the pathogen's elimination are unknown. In this study, we identify Irga6 as an important resistance factor against C. trachomatis, but not C. muridarum, infection in IFNgamma-stimulated mouse embryonic fibroblasts (MEFs). We show that Irga6, Irgd, Irgm2 and Irgm3 accumulate at bacterial inclusions in MEFs upon stimulation with IFNgamma, whereas Irgb6 colocalized in the presence or absence of the cytokine. This accumulation triggers a rerouting of bacterial inclusions to autophagosomes that subsequently fuse to lysosomes for elimination. Autophagy-deficient Atg5-/- MEFs and lysosomal acidification impaired cells surrender to infection. Irgm2, Irgm3 and Irgd still localize to inclusions in IFNgamma-induced Atg5-/- cells, but Irga6 localization is disrupted indicating its pivotal role in pathogen resistance. Irga6-deficient (Irga6-/-) MEFs, in which chlamydial growth is enhanced, do not respond to IFNgamma even though Irgb6, Irgd, Irgm2 and Irgm3 still localize to inclusions. Taken together, we identify Irga6 as a necessary factor in conferring host resistance by remodelling a classically nonfusogenic intracellular pathogen to stimulate fusion with autophagosomes, thereby rerouting the intruder to the lysosomal compartment for destruction.
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: Peter R
authors.initials: PR
authors.lastname: Braun
authors.forename: Jens
authors.initials: J
authors.lastname: Zerrahn
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Meyer
mesh_terms: D000818:Animals; D001343:Autophagy / Q000276:immunology*; D002478:Cells, Cultured; D002690:Chlamydia Infections / Q000276:immunology; D023502:Chlamydia muridarum / Q000276:immunology; D002692:Chlamydia trachomatis / Q000276:immunology*; D005347:Fibroblasts / Q000382:microbiology; D020558:GTP Phosphohydrolases / Q000276:immunology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D002479:Inclusion Bodies / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D008247:Lysosomes / Q000378:metabolism; D051379:Mice
chemical_list: C096000:Ifi1 protein, mouse; D007371:Interferon-gamma; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; C491070:Iigp1 protein, mouse