Cell-specific Activation of Nuclear Factor-kB by the Parasite Trypanosoma cruzi Promotes Resistance to Intracellular Infection

The transcription factor nuclear factor-kB (NF-kB) is central to the innate and acquired immune response to microbial pathogens, coordinating cellular responses to the presence of infection. Here we demonstrate a direct role for NF-kB activation in controlling intracellular infection in nonimmune cells. Trypanosoma cruzi is an intracellular parasite of mammalian cells with a marked preference for infection of myocytes. The molecular basis for this tissue tropism is unknown. Trypomastigotes, the infectious stage of T. cruzi, activate nuclear translocation and DNA binding of NF-kB p65 subunit and NF-kB-dependent gene expression in epithelial cells, endothelial cells, and fibroblasts. Inactivation of epithelial cell NF-kB signaling by inducible expression of the inhibitory mutant IkBaM significantly enhances parasite invasion. T. cruzi do not activate NF-kB in cells derived from skeletal, smooth, or cardiac muscle, despite the ability of these cells to respond to tumor necrosis factor-a with NF-kB activation. The in vitro infection level in these muscle-derived cells is more than double that seen in the other cell types tested. Therefore, the ability of T. cruzi to activate NF-kB correlates inversely with susceptibility to infection, suggesting that NF-kB activation is a determinant of the intracellular survival and tissue tropism of T. cruzi.