title: NFATc1 mediates Toll-like receptor-independent innate immune responses during Trypanosoma cruzi infection.
abstract: Host defense against the intracellular protozoan parasite Trypanosoma cruzi depends on Toll-like receptor (TLR)-dependent innate immune responses. Recent studies also suggest the presence of TLR-independent responses to several microorganisms, such as viruses, bacteria, and fungi. However, the TLR-independent responses to protozoa remain unclear. Here, we demonstrate a novel TLR-independent innate response pathway to T. cruzi. Myd88(-/-)Trif(-/-) mice lacking TLR signaling showed normal T. cruzi-induced Th1 responses and maturation of dendritic cells (DCs), despite high sensitivity to the infection. IFN-gamma was normally induced in T. cruzi-infected Myd88(-/-)Trif(-/-) innate immune cells, and further was responsible for the TLR-independent Th1 responses and DC maturation after T. cruzi infection. T. cruzi infection induced elevation of the intracellular Ca(2+) level. Furthermore, T. cruzi-induced IFN-gamma expression was blocked by inhibition of Ca(2+) signaling. NFATc1, which plays a pivotal role in Ca(2+) signaling in lymphocytes, was activated in T. cruzi-infected Myd88(-/-)Trif(-/-) innate immune cells. T. cruzi-infected Nfatc1(-/-) fetal liver DCs were impaired in IFN-gamma production and DC maturation. These results demonstrate that NFATc1 mediates TLR-independent innate immune responses in T. cruzi infection.
authors.affiliation: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Kayama
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Koga
authors.forename: Koji
authors.initials: K
authors.lastname: Atarashi
authors.forename: Megumi
authors.initials: M
authors.lastname: Okuyama
authors.forename: Taishi
authors.initials: T
authors.lastname: Kimura
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takayanagi
authors.forename: Kenya
authors.initials: K
authors.lastname: Honda
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D000818:Animals; D020013:Calcium Signaling / Q000276:immunology; D002478:Cells, Cultured; D014355:Chagas Disease / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D003627:Data Interpretation, Statistical; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D050778:NFATC Transcription Factors / Q000276:immunology*; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology; D014349:Trypanosoma cruzi
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D007371:Interferon-gamma; D053594:Myeloid Differentiation Factor 88; D050778:NFATC Transcription Factors; D051193:Toll-Like Receptors; C507780:Myd88 protein, mouse; C494005:Nfatc1 protein, mouse; C476286:Ticam1 protein, mouse