TRYPANOSOME INVASION OF MAMMALIAN-CELLS REQUIRES ACTIVATION OF THE TGF-BETA SIGNALING PATHWAY

Trypanosoma cruzi invades most nucleated mammalian cells by as yet unk nown mechanisms, We report here that while T. cruzi attaches to epithe lial cells lacking signaling transforming growth factor beta (TGF beta ) receptor I or II, the adherent parasites cannot penetrate and replic ate inside the mutant cells, as they do in parental cells, Invasion of the mutants is restored by transfection with the TGF beta receptor ge nes, as are biological responses to TGF beta. Similar rescue of both T GF beta antiproliferative response and T. cruzi invasion was demonstra ted in a hybrid of TGF beta-resistant bladder and colon carcinoma cell s. In addition, T. cruzi did not efficiently invade epithelial cells w ith dysfunction of the intracellular signaling cascade caused by the c onstitutive expression of the cyclin-dependent kinase cdk4 or of the o ncogene H-ras. Treatment with TGF beta, but not with other antiprolife rative agents of nonphagocytic cells, greatly enhances T. cruzi invasi on. Moreover, infective, but not noninfective, trypanosomes strongly i nduce a TGF beta-responsive reporter gene in TGF beta-sensitive, but n ot in TGF beta-insensitive, cell lines. Thus, T. cruzi itself may dire ctly trigger activation of the TGF beta signaling pathway required for parasite entry into the mammalian cells.