Trypanosome invasion of mammalian cells requires activation of the TGFβ signaling pathway

Abstract

Trypanosoma cruzi invades most nucleated mammalian cells by as yet unknown mechanisms. We report here that while T. cruzi attaches to epithelial cells lacking signaling transforming growth factor beta (TGF beta) receptor I or II, the adherent parasites cannot penetrate and replicate inside the mutant cells, as they do in parental cells. Invasion of the mutants is restored by transfection with the TGF beta receptor genes, as are biological responses to TGF beta. Similar rescue of both TGF beta antiproliferative response and T. cruzi invasion was demonstrated in a hybrid of TGF beta-resistant bladder and colon carcinoma cells. In addition, T. cruzi did not efficiently invade epithelial cells with dysfunction of the intracellular signaling cascade caused by the constitutive expression of the cyclin-dependent kinase cdk4 or of the oncogene H-ras. Treatment with TGF beta, but not with other antiproliferative agents of non-phagocytic cells, greatly enhances T. cruzi invasion. Moreover, infective, but not noninfective, trypanosomes strongly induce a TGF beta-responsive reporter gene in TGF beta-sensitive, but not in TGF beta-insensitive, cell lines. Thus, T. cruzi itself may directly trigger activation of the TGF beta signaling pathway required for parasite entry into the mammalian cells.

Trypanosoma cruzitrans-sialidase: A potent and specific survival factor for human Schwann cells by means of phosphatidylinositol 3-kinase/Akt signaling

“…It is generally accepted that T. cruzi infection of epithelial cells, fibroblasts, and other cells leads to the death of host cells (8)(9)(10). However, we report here that T. cruzi invasion of Schwann cells does not initially result in cell death.…”

“…After 2 hr, unattached parasites were removed by washing, and the cells were switched to serum-free medium for 72 hr. Intracellular parasites were identified by Giemsa staining or indirect immunofluorescence with chagasic IgG as primary antibody (10) and Alexa 594-labeled second antibody (Molecular Probes).…”

A role for extracellular amastigotes in the immunopathology of Chagas disease

“…Once released from disrupted cells, the trypomastigotes spread the infection via the bloodstream and/or lymphatics. At this early stage of infection, a wide range of non-phagocytic host cells can be invaded by the trypomastigotes, but host cell target preference can differ markedly from one parasite clone to another due to the variable composition and expression levels of their cell surface adhesion molecules, some of which are highly polymorphic (Affranchino et al 1989, Tackle & Cross 1991, Colli 1993, Schenckman et al 1994, Giordanno et al 1994, Pereira et al 1996, Salazar et al 1996 or due to differential signaling ability of the invading parasite clones (Ming et al 1995, Burleigh & Andrews 1998.…”

A century of research: what have we learned about the interaction of Trypanosoma cruzi with host cells?

“…�nother mechanism for the attachment-independent invasion of trypomastigotes phase involves the activaphase involves the activation of the TGFβ signalling pathway (Silva et al 1991, Ming et al 1995, �raujo-Jorge et al 2008). The agent involved in mediating the signalling remains elusive, but it seems to be thermo-labile and hydrophobic in nature.…”