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

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26 Citations (Scopus)

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-γ 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 Ca2+ level. Furthermore, T. cruzi-induced IFN-γ expression was blocked by inhibition of Ca2+ signaling. NFATc1, which plays a pivotal role in Ca2+ 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-γ production and DC maturation. These results demonstrate that NFATc1 mediates TLR-independent innate immune responses in T. cruzi infection.

Original languageEnglish
Article numbere1000514
JournalPLoS Pathogens
Volume5
Issue number7
DOIs
Publication statusPublished - 2009 Jul

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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    Kayama, H., Koga, R., Atarashi, K., Okuyama, M., Kimura, T., Mak, T. W., Uematsu, S., Akira, S., Takayanagi, H., Honda, K., Yamamoto, M., & Takeda, K. (2009). NFATc1 mediates toll-like receptor-independent innate immune responses during Trypanosoma cruzi infection. PLoS Pathogens, 5(7), [e1000514]. https://doi.org/10.1371/journal.ppat.1000514