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PMID: 19242543 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

IFN-gamma-inducible Irga6 mediates host resistance against Chlamydia trachomatis via autophagy.

PloS one ·Vol. 4 ·No. 2 ·2009-00-00 ·Pages e4588

Al-Zeer MA, Al-Younes HM, Braun PR, Zerrahn J, Meyer TF

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.

MeSH Terms
Animals Autophagy/immunology Cells, Cultured Chlamydia Infections/immunology Chlamydia muridarum/immunology Chlamydia trachomatis/immunology Fibroblasts/microbiology GTP Phosphohydrolases/immunology GTP-Binding Proteins/metabolism Inclusion Bodies/metabolism Interferon-gamma/pharmacology Lysosomes/metabolism Mice
Chemicals
Ifi1 protein, mouse Interferon-gamma GTP Phosphohydrolases GTP-Binding Proteins Iigp1 protein, mouse
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Al-Zeer Munir A
Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
Al-Younes Hesham M
Braun Peter R
Zerrahn Jens
Meyer Thomas F
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Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0004588
Published
2009-00-00
Epub
2009-00-26
Pages
e4588
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC2643846
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pone.0004588 PMC Full Text View journal details
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