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* Department of Molecular Genetics, Medical Institute of Bioregulation and
Department of Parasitology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan; and
Department of Host Defense, Institute for Microbial Diseases, Osaka University, and Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Suita, Japan
Host resistance to the intracellular protozoan parasite Trypanosoma cruzi depends on IFN-
production by T cells and NK cells. However, the involvement of innate immunity in host resistance to T. cruzi remains unclear. In the present study, we investigated host defense against T. cruzi by focusing on innate immunity. Macrophages and dendritic cells (DCs) from MyD88–/–TRIF–/– mice, in which TLR-dependent activation of innate immunity was abolished, were defective in the clearance of T. cruzi and showed impaired induction of IFN-β during T. cruzi infection. Neutralization of IFN-β in MyD88–/– macrophages led to enhanced T. cruzi growth. Cells from MyD88–/–IFNAR1–/– mice also showed impaired T. cruzi clearance. Furthermore, both MyD88–/–TRIF–/– and MyD88–/–IFNAR1–/– mice were highly susceptible to in vivo T. cruzi infection, highlighting the involvement of innate immune responses in T. cruzi infection. We further analyzed the molecular mechanisms for the IFN-β-mediated antitrypanosomal innate immune responses. MyD88–/–TRIF–/– and MyD88–/–IFNAR1–/– macrophages and DCs exhibited defective induction of the GTPase IFN-inducible p47 (IRG47) after T. cruzi infection. RNA interference-mediated reduction of IRG47 expression in MyD88–/– macrophages resulted in increased intracellular growth of T. cruzi. These findings suggest that TLR-dependent expression of IFN-β is involved in resistance to T. cruzi infection through the induction of IRG47.
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1 This work was supported by grants from the Special Coordination Funds of the Ministry of Education, Culture, Sports, Science and Technology, as well as the Uehara Memorial Foundation, the Mitsubishi Foundation, the Takeda Science Foundation, the Tokyo Biochemical Research Foundation, the Kowa Life Science Foundation, the Osaka Foundation for Promotion of Clinical Immunology, and the Sankyo Foundation of Life Science.
2 Address correspondence and reprint requests to Dr. Kiyoshi Takeda, Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail address: ktakeda{at}bioreg.kyushu-u.ac.jp
3 Abbreviations used in this paper: DC, dendritic cell; TIR, Toll/IL-1R; TRIF, TIR domain-containing adaptor-inducing IFN-β; WT, wild type; siRNA, small interfering RNA; EF-1
, elongation factor-1.
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