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.
Highlights
The host defense against invasion of intracellular pathogens relies on Th1 cell-derived IFN-c that activates macrophages to kill the engulfed pathogens [1]
These results demonstrate that NFATc1 mediates Toll-like receptor (TLR)-independent innate immune responses in T. cruzi infection
Our results demonstrate that NFATc1 mediates TLR-independent induction of IFN-c in innate immune cells, leading to effective Th1 responses during T. cruzi infection
Summary
The host defense against invasion of intracellular pathogens relies on Th1 cell-derived IFN-c that activates macrophages to kill the engulfed pathogens [1]. Several components of T. cruzi have been shown to induce TLR-dependent activation of innate immunity and subsequent development of Th1 cells [9,10,11,12,13,14]. Invasion of infective metacyclic trypomastigotes of T. cruzi into host cells induces a close interaction between the parasites and the host, because T. cruzi utilize several host-derived factors in order to establish the infection. These include activation of Ca2+ signaling pathways and phosphatidylinositol-3 kinases [18,19,20]. It remains unclear how T. cruzi-mediated activation of host cytoplasmic signaling pathways is regulated and whether it is TLRdependent or -independent
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