Kayama Hisako, Koga Ritsuko, Atarashi Koji, Okuyama Megumi, Kimura Taishi, Mak Tak W, Uematsu Satoshi, Akira Shizuo, Takayanagi Hiroshi, Honda Kenya, Yamamoto Masahiro, Takeda Kiyoshi
Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
PLoS Pathog. 2009 Jul;5(7):e1000514. doi: 10.1371/journal.ppat.1000514. Epub 2009 Jul 17.
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.
宿主对细胞内原生动物寄生虫克氏锥虫的防御依赖于Toll样受体（TLR）依赖性先天免疫反应。最近的研究还表明，存在对几种微生物（如病毒、细菌和真菌）的非TLR依赖性反应。然而，对原生动物的非TLR依赖性反应仍不清楚。在此，我们展示了一种针对克氏锥虫的新型非TLR依赖性先天反应途径。缺乏TLR信号传导的Myd88(-/-)Trif(-/-)小鼠尽管对感染高度敏感，但对克氏锥虫诱导的Th1反应和树突状细胞（DC）成熟表现正常。在感染克氏锥虫的Myd88(-/-)Trif(-/-)先天免疫细胞中，IFN-γ正常诱导产生，并且进一步介导了克氏锥虫感染后的非TLR依赖性Th1反应和DC成熟。克氏锥虫感染导致细胞内Ca(2+)水平升高。此外，克氏锥虫诱导的IFN-γ表达被Ca(2+)信号传导的抑制所阻断。在淋巴细胞Ca(2+)信号传导中起关键作用的NFATc1在感染克氏锥虫的Myd88(-/-)Trif(-/-)先天免疫细胞中被激活。感染克氏锥虫的Nfatc1(-/-)胎肝DC在IFN-γ产生和DC成熟方面受损。这些结果表明，NFATc1在克氏锥虫感染中介导非TLR依赖性先天免疫反应。
