Abstract
Patients infected with Trypanosoma cruzi may remain asymptomatic for decades and show signs of neuroregeneration in the peripheral nervous system (PNS). In the absence of such neuroregeneration, patients may die in part by extensive neuronal destruction in the gastrointestinal tract. Thus, T. cruzi may, despite their invasion of the PNS, directly prevent cell death to keep nerve destruction in check. Indeed, T. cruzi invasion of Schwann cells, their prime target in PNS, suppressed host-cell apoptosis caused by growth-factor deprivation. The trans-sialidase (TS) of T. cruzi and the Cys-rich domain of TS reproduced the antiapoptotic activity of the parasites at doses (> or =3.0 nM) comparable or lower than those of bona fide mammalian growth factors. This effect was blocked by LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K). TS also activated Akt, a downstream effector of PI3K. Ectopic expression of TS in an unrelated parasite, Leishmania major, turned those parasites into activators of Akt in Schwann cells. In contrast, the Cys-rich domain of TS did not block apoptosis in Schwann cells overexpressing dominant-negative Akt or constitutively active PTEN, a negative regulator of PI3K/Akt signaling. The results demonstrate that T. cruzi, through its TS, triggers the survival of host Schwann cells via the PI3K/Akt pathway, suggesting a role for PI3K/Akt in the pathogenesis of Chagas' disease.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects
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Cell Survival / drug effects
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Cells, Cultured
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Chagas Disease / enzymology
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Chromones / pharmacology
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Culture Media, Serum-Free / pharmacology
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Glycoproteins / genetics
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Glycoproteins / pharmacology*
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Glycoproteins / physiology
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Humans
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Leishmania major / enzymology
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Molecular Sequence Data
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Morpholines / pharmacology
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Neuraminidase / genetics
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Neuraminidase / pharmacology*
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Neuraminidase / physiology
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PTEN Phosphohydrolase
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Phosphatidylinositol 3-Kinases / physiology*
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoric Monoester Hydrolases / genetics
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Phosphoric Monoester Hydrolases / physiology
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Phosphorylation
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Protein Processing, Post-Translational
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / deficiency
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-akt
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Protozoan Proteins / pharmacology*
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Recombinant Fusion Proteins / physiology
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Schwann Cells / cytology
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Schwann Cells / drug effects*
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Schwann Cells / parasitology
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Signal Transduction / drug effects*
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Transfection
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Trypanosoma cruzi / enzymology*
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Trypanosoma cruzi / pathogenicity
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Tumor Suppressor Proteins*
Substances
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Chromones
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Culture Media, Serum-Free
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Enzyme Inhibitors
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Glycoproteins
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Protozoan Proteins
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Recombinant Fusion Proteins
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Tumor Suppressor Proteins
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase
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PTEN protein, human
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trans-sialidase
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Neuraminidase