IFN-[gamma]-Inducible Irga6 Mediates Host Resistance against Chlamydia trachomatis via Autophagy

• Published in: PloS one Vol. 4; no. 2; p. e4588
• Main Authors: Al-Zeer, Munir A, Al-Younes, Hesham M, Braun, Peter R, Zerrahn, Jens, Meyer, Thomas F
• Format: Journal Article
• Language: English
• Published: Public Library of Science 26.02.2009
• Subjects: Biological response modifiers; Chlamydia; Chlamydia infections; Health aspects; Infection; Interferon; Microbial drug resistance
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0004588

Chlamydial infection of the host cell induces Gamma interferon (IFN[gamma]), a central immunoprotector for humans and mice. The primary defense against Chlamydia infection in the mouse involves the IFN[gamma]-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 IFN[gamma]-stimulated mouse embryonic fibroblasts (MEFs). We show that Irga6, Irgd, Irgm2 and Irgm3 accumulate at bacterial inclusions in MEFs upon stimulation with IFN[gamma], 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 IFN[gamma]-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 IFN[gamma] 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.