PLoS Pathogens (Jul 2009)

NFATc1 mediates Toll-like receptor-independent innate immune responses during Trypanosoma cruzi infection.

  • Hisako Kayama,
  • Ritsuko Koga,
  • Koji Atarashi,
  • Megumi Okuyama,
  • Taishi Kimura,
  • Tak W Mak,
  • Satoshi Uematsu,
  • Shizuo Akira,
  • Hiroshi Takayanagi,
  • Kenya Honda,
  • Masahiro Yamamoto,
  • Kiyoshi Takeda

DOI
https://doi.org/10.1371/journal.ppat.1000514
Journal volume & issue
Vol. 5, no. 7
p. e1000514

Abstract

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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.