Cell-specific activation of nuclear factor-kappaB by the parasite Trypanosoma cruzi promotes resistance to intracellular infection.

The transcription factor nuclear factor-kappaB (NF-kappaB) 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-kappaB 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-kappaB p65 subunit and NF-kappaB-dependent gene expression in epithelial cells, endothelial cells, and fibroblasts. Inactivation of epithelial cell NF-kappaB signaling by inducible expression of the inhibitory mutant IkappaBaM significantly enhances parasite invasion. T. cruzi do not activate NF-kappaB in cells derived from skeletal, smooth, or cardiac muscle, despite the ability of these cells to respond to tumor necrosis factor-alpha with NF-kappaB 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-kappaB correlates inversely with susceptibility to infection, suggesting that NF-kappaB activation is a determinant of the intracellular survival and tissue tropism of T. cruzi.