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.
Hall
B S
BS
Parasitology Research Center, Department of Pathology, Tufts University Medical School, Boston, Massachusetts 02111, USA.
Tam
W
W
Sen
R
R
Pereira
M E
ME
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D007424:Intracellular Fluid / Q000469:parasitology; D008907:Mink; D016328:NF-kappa B / Q000378:metabolism*; D051996:Transcription Factor RelA; D014349:Trypanosoma cruzi / Q000378:metabolism / Q000502:physiology*
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D051996:Transcription Factor RelA