Signaling pathways involved in type I IFN production in T. cruzi infected cells

The signaling pathways responsible for induction of type I IFN production by host cells during T. cruzi infection have not been fully characterized. The process has been shown to depend on IRF3/TBK1 (as all known pathways leading to IFN-a and -в production), and to follow the dynamics of an autocrine induction loop.83 Additionally, type I IFN production by host cells is known to be elicited before T. cruzi escapes the parasitophorous vacuole, and can take place in the absence of active infection (since heat-killed trypomastigotes also triggered it).83

Despite earlier indications of TLR3 involvement,84 Chessler et al.83 found no evidence for TLR-signaling in the process by exploiting mouse fibroblasts (MEFs) and mouse bone marrow-derived macrophages (BMDM) defective for TLR3, TLR4, and their downstream mediators Myd88 and TRIF. Moreover, the cytosolic sensors known at the time (RIG-I and MDA5) were also not required during T. cruzi- induced type I IFN production. A possible role for more recently discovered cytoplasmic sensing mechanisms82,85 remains to be studied. Additionally, it is tempting to speculate that Ca21 signaling associated to perturbations of host cell membrane could activate IRF3, causing type I IFN production during T. cruzi cell invasion, as it has been shown to occur during viral infection.86

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