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* Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115; and
Division of Infectious Disease and Immunology, University of Massachusetts Medical School, Worcester, MA 01605
Innate immune recognition of intracellular pathogens involves both extracellular and cytosolic surveillance mechanisms. The intracellular protozoan parasite Trypanosoma cruzi triggers a robust type I IFN response in both immune and nonimmune cell types. In this study, we report that signaling through TBK1 and IFN regulatory factor 3 is required for T. cruzi-mediated expression of IFN-β. The TLR adaptors MyD88 and TRIF, as well as TLR4 and TLR3, were found to be dispensable, demonstrating that T. cruzi induces IFN-β expression in a TLR-independent manner. The potential role for cytosolic dsRNA sensing pathways acting through RIG-I and MDA5 was ruled out because T. cruzi was shown to trigger robust expression of IFN-β in macrophages lacking the MAVS/IPS1/VISA/CARDif adaptor protein. The failure of T. cruzi to activate HEK293-IFN-β-luciferase cells, which are highly sensitive to cytosolic triggers of IFN-β expression including Listeria, Sendai virus, and transfected dsRNA and dsDNA, further indicates that the parasite does not engage currently recognized cytosolic surveillance pathways. Together, these findings identify the existence of a novel TLR-independent pathogen-sensing mechanism in immune and nonimmune cells that converges on TBK1 and IFN regulatory factor 3 for activation of IFN-β gene expression.
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 Grant AI047960 (to B.A.B.) and AI067497 (to K.A.F.).
2 Address correspondence and reprint requests to Dr. Barbara A. Burleigh, Department of Immunology and Infectious Diseases, Harvard School of Public Health, Building I, Room 817, 665 Huntington Avenue, Boston MA 02115. E-mail address: bburleig{at}hsph.harvard.edu
3 Abbreviations used in this paper: IRF, IFN regulatory factor; DAI, DNA-dependent activator of IRF; TBK1, TANK-binding kinase 1; IFNAR, type I IFN receptor; MEF, mouse embryonic fibroblast; WT, wild type; Pen-Strep, penicillin-streptomycin; BMDM, bone marrow-derived macrophage; qRT-PCR, quantitative RT-PCR.
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