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Department of Microbiology and Immunology, University of California, San Francisco, CA 94158
The ESX-1 secretion system is a major determinant of Mycobacterium tuberculosis virulence, although the pathogenic mechanisms resulting from ESX-1-mediated transport remain unclear. By global transcriptional profiling of tissues from mice infected with either wild-type or ESX-1 mutant bacilli, we found that host genes controlled by ESX-1 in vivo are predominantly IFN regulated. ESX-1-mediated secretion is required for the production of host type I IFNs during infection in vivo and in macrophages in vitro. The macrophage signaling pathway leading to the production of type I IFN required the host kinase TANK-binding kinase 1 and occurs independently of TLR signaling. Importantly, the induction of type I IFNs during M. tuberculosis infection is a pathogenic mechanism as mice lacking the type I IFNR were more restrictive for bacterial growth in the spleen than wild-type mice, although growth in the lung was unaffected. We propose that the ESX-1 secretion system secretes effectors into the cytosol of infected macrophages, thereby triggering the type I IFN response for the manipulation of host immunity.
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 AI63302 and AI51667 (to J.S.C.). J.S.C. gratefully acknowledges the support of the Sandler Family Supporting Foundation and the W. M. Keck Foundation.
2 Address correspondence and reprint requests to Dr. Jeffery S. Cox, Department of Microbiology and Immunology; University of California, San Francisco, MBGH N372B, San Francisco, CA 94158. E-mail address: jeffery.cox{at}ucsf.edu
3 Abbreviations used in this paper: IFNAR1, IFNR
1; BMDM, bone marrow-derived macrophage; CFP-10, culture filtrate protein-10; ESAT-6, early secreted antigenic target-6; IP-10, IFN-
-inducible protein-10; IRF, IFN regulatory factor; MEEBO, Mouse Exonic Evidence-Based Oligonucleotide; MOI, multiplicity of infection; Nod, nucleotide-binding oligomerization domain protein; RIP2, receptor-interacting protein 2; SAM, Statistical Analysis of Microarray; TBK1, TANK-binding kinase 1; WT, wild type.
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