title: Chlamydia muridarum evades growth restriction by the IFN-gamma-inducible host resistance factor Irgb10.
abstract: Chlamydiae are obligate intracellular bacterial pathogens that exhibit a broad range of host tropism. Differences in host tropism between Chlamydia species have been linked to host variations in IFN-gamma-mediated immune responses. In mouse cells, IFN-gamma can effectively restrict growth of the human pathogen Chlamydia trachomatis but fails to control growth of the closely related mouse pathogen Chlamydia muridarum. The ability of mouse cells to resist C. trachomatis replication is largely dependent on the induction of a family of IFN-gamma-inducible GTPases called immunity-related GTPases or IRGs. In this study we demonstrate that C. muridarum can specifically evade IRG-mediated host resistance. It has previously been suggested that C. muridarum inactivates the IRG protein Irga6 (Iigp1) to dampen the murine immune response. However, we show that Irga6 is dispensable for the control of C. trachomatis replication. Instead, an effective IFN-gamma response to C. trachomatis requires the IRG proteins Irgm1 (Lrg47), Irgm3 (Igtp), and Irgb10. Ectopic expression of Irgb10 in the absence of IFN-gamma is sufficient to reduce intracellular growth of C. trachomatis but fails to restrict growth of C. muridarum, indicating that C. muridarum can specifically evade Irgb10-driven host responses. Importantly, we find that Irgb10 protein intimately associates with inclusions harboring C. trachomatis but is absent from inclusions formed by C. muridarum. These data suggest that C. muridarum has evolved a mechanism to escape the murine IFN-gamma response by restricting access of Irgb10 and possibly other IRG proteins to the inclusion.
authors.affiliation: Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Jörn
authors.initials: J
authors.lastname: Coers
authors.forename: Isaac
authors.initials: I
authors.lastname: Bernstein-Hanley
authors.forename: David
authors.initials: D
authors.lastname: Grotsky
authors.forename: Iana
authors.initials: I
authors.lastname: Parvanova
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Howard
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Taylor
authors.forename: William F
authors.initials: WF
authors.lastname: Dietrich
authors.forename: Michael N
authors.initials: MN
authors.lastname: Starnbach
mesh_terms: D000818:Animals; D005075:Biological Evolution; D002478:Cells, Cultured; D002690:Chlamydia Infections / Q000235:genetics / Q000276:immunology*; D023502:Chlamydia muridarum / Q000254:growth & development / Q000276:immunology*; D002692:Chlamydia trachomatis / Q000254:growth & development / Q000276:immunology; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate / Q000235:genetics; D002479:Inclusion Bodies / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D007371:Interferon-gamma; D020558:GTP Phosphohydrolases; C491070:Iigp1 protein, mouse; C515445:Irgb10 protein, mouse