title: TLR-dependent induction of IFN-beta mediates host defense against Trypanosoma cruzi.
abstract: Host resistance to the intracellular protozoan parasite Trypanosoma cruzi depends on IFN-gamma 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-beta during T. cruzi infection. Neutralization of IFN-beta 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-beta-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-beta is involved in resistance to T. cruzi infection through the induction of IRG47.
authors.affiliation: Department of Molecular Genetics, Medical Institute of Bioregulation, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Koga
authors.forename: Shinjiro
authors.initials: S
authors.lastname: Hamano
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Kuwata
authors.forename: Koji
authors.initials: K
authors.lastname: Atarashi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ogawa
authors.forename: Hajime
authors.initials: H
authors.lastname: Hisaeda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Kunisuke
authors.initials: K
authors.lastname: Himeno
authors.forename: Makoto
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D014355:Chagas Disease / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D020558:GTP Phosphohydrolases / Q000096:biosynthesis / Q000502:physiology; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000502:physiology; D005786:Gene Expression Regulation / Q000276:immunology; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000502:physiology; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis* / Q000502:physiology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics; D051193:Toll-Like Receptors / Q000502:physiology*; D014349:Trypanosoma cruzi / Q000254:growth & development / Q000276:immunology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D006131:Growth Inhibitors; D018836:Inflammation Mediators; D016899:Interferon-beta; D053594:Myeloid Differentiation Factor 88; D053633:Receptor, Interferon alpha-beta; D051193:Toll-Like Receptors; C096000:Ifi1 protein, mouse; C508032:Ifnar1 protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse