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Chlamydia muridarum Evades Growth Restriction by the IFN--Inducible Host Resistance Factor Irgb10¹

Jörn Coers^*, Isaac Bernstein-Hanley^*, David Grotsky^*, Iana Parvanova, Jonathan C. Howard, Gregory A. Taylor^,¶, William F. Dietrich^|| and Michael N. Starnbach^2,*

^* Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115; Department of Molecular Pathology, University of Bern, Bern, Switzerland; Institute for Genetics, University of Cologne, Cologne, Germany; Departments of Medicine, Molecular Genetics and Microbiology, and Immunology, and Center for the Study of Aging, Duke University, Durham, NC 27708; ^¶ Geriatric Research and Education and Clinical Center, Veteran Affairs Medical Center, Durham, NC 27710; and ^|| Mouse Genetics and Toxicology Models of Disease Center, Novartis Institutes for BioMedical Research, Cambridge, MA 02139

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--mediated immune responses. In mouse cells, IFN- 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--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- response to C. trachomatis requires the IRG proteins Irgm1 (Lrg47), Irgm3 (Igtp), and Irgb10. Ectopic expression of Irgb10 in the absence of IFN- 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- response by restricting access of Irgb10 and possibly other IRG proteins to the inclusion.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI062827 (to M.N.S.), AI57831 (to G.A.T.), a Veteran Affairs Merit Review Grant (to G.A.T.), and the SFB670 Grant "Cell Autonomous Immunity" (to J.C.H.). J.C. was supported by a research fellowship from the Deutsche Forschungsgemeinschaft and by the Charles A. King Trust Postdoctoral Research Fellowship.

² Address correspondence and reprint requests to Dr. Michael N. Starnbach, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115. E-mail address: starnbach{at}hms.harvard.edu

³ Abbreviations used in this paper: IRG, immunity-related GTPase; B6, C57BL/6; hpi, hours postinfection; MEF, mouse embryonic fibroblast; MOI, multiplicity of infection; MOMP, major outer membrane protein; RNAi, RNA interference.

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