A trypanosomal protein synergizes with the cytokines ciliary neurotrophic factor and leukemia inhibitory factor to prevent apoptosis of neuronal cells.
Despite the neuronal degeneration in the chronic stage of Chagas' disease, neuron counts actually increase in the preceding, asymptomatic stage, in contrast to the age-related decrease in neuron counts in age-matched normal individuals. Relevant to this observation, we found that the trans-sialidase (TS) of Trypanosoma cruzi, the etiologic agent of Chagas' disease, induces neurite outgrowth and rescues PC12 cells from apoptotic death caused by growth factor deprivation. These properties, novel for a parasite protein, were independent of catalytic activity and were mapped to the C terminus of the catalytic domain of TS. TS activated protein kinase Akt in a phosphoinositide-3 kinase-inhibitable manner, suggesting a molecular mechanism for the TS-induced neuroprotection. TS also triggered bcl-2 gene expression in growth factor-deprived cells, an effect consistent with TS protecting against apoptosis. Ciliary neurotrophic factor and leukemia inhibitory factor, two cytokines critical to the repair of injured motor neurons, specifically potentiated the TS action. The results suggest that TS acts in synergy with host ciliary neurotrophic factor or leukemia inhibitory factor to promote neuronal survival in T. cruzi-infected individuals.
Chuenkova
M V
MV
Parasitology Research Center, Department of Pathology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Pereira
M A
MA
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D020934:Ciliary Neurotrophic Factor / Q000378:metabolism*; D004789:Enzyme Activation; D006023:Glycoproteins / Q000378:metabolism*; D006131:Growth Inhibitors / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000378:metabolism*; D009439:Neuraminidase / Q000378:metabolism*; D016501:Neurites / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism / Q000648:ultrastructure; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014349:Trypanosoma cruzi / Q000201:enzymology* / Q000378:metabolism
D020934:Ciliary Neurotrophic Factor; D006023:Glycoproteins; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D009439:Neuraminidase; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; C507837:LIF protein, human; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; C069715:trans-sialidase