Dual role for transforming growth factor beta-dependent signaling in Trypanosoma cruzi infection of mammalian cells.

Abstract

Expression of functional transforming growth factor beta (TGF-beta) receptors (TbetaR) is required for the invasion of mammalian cells by the protozoan parasite Trypanosoma cruzi. However, the precise role of this host cell signaling complex in T. cruzi infection is unknown. To investigate the role of the TGF-beta signaling pathway, infection levels were studied in the mink lung epithelial cell lines JD1, JM2, and JM3. These cells express inducible mutant TbetaR1 proteins that cannot induce growth arrest in response to TGF-beta but still transmit the signal for TGF-beta-dependent gene expression. In the absence of mutant receptor expression, trypomastigotes invaded the cells at a low level. Induction of the mutant receptors caused an increase in infection in all three cell lines, showing that the requirement for TGF-beta signaling at invasion can be divorced from TGF-beta-induced growth arrest. TGF-beta pretreatment of mink lung cells expressing wild-type TbetaR1 caused a marked enhancement of infection, but no enhancement was seen in JD1, JM2, and JM3 cells, showing that the ability of TGF-beta to stimulate infection is associated with growth arrest. Likewise, expression of SMAD7 or SMAD2SA, inhibitors of TGF-beta signaling, did not block infection by T. cruzi but did block the enhancement of infection by TGF-beta. Taken together, these results show that there is a dual role for TGF-beta signaling in T. cruzi infection. The initial invasion of the host cell is independent of both TGF-beta-dependent gene expression and growth arrest, but TGF-beta stimulation of infection requires a fully functional TGF-beta signaling pathway.