Patients with Chagas' disease, caused by the protozoan Trypanosoma cruzi, exhibit an acute stage, characterized by robust parasite growth and neural degeneration; an asymptomatic indeterminate chronic phase, marked by the regeneration of neurons; and a chronic phase, designated by immunological alterations and tremendous degeneration of neurons. Most patients remain in the indeterminate phase for years or decades. Some asymptomatic patients progress to the chronic, fatal chronic disease stage. It remains a mystery why patients can remain asymptomatic and with signs of neural regeneration for life while others develop neuro-degeneration. Recent studies demonstrate that the trans-sialidase (TS) of T. cruzi is a potent survival factor for several types of neurons, and for glial Schwann cells and astrocytes. TS can be as good as nerve growth factor (NGF) in protecting sympathetic-like PC12 cells against apoptosis provoked by starvation. In addition, TS synergizes with cytokines of the interleukin-6 family to protect neurons. Likewise, TS is as good as neureglin and other growth factors that promote survival of glial Schwann cells. Yet, TS has no detectable homology to NGF and other neutrophins, and to cytokine neurotrophic factors. Thus, it remains unknown how TS promotes survival of neurons and glial cells. The best way to understand T. cruzi-induced survival is to know the nature of the receptors TS react with on neurons and glial cells. This project attempts to identify TS receptors that T. cruzi uses to promote cell survival during invasion of the nervous system. The project will utilize a state-or-the-art combination of cell biology, biochemistry, genetics, and immunochemical approaches to identify and characterize relevant receptors. The outcome of the studies could very well provide insights into the pathogenesis of Chagas' disease and to lead to the development of compounds to treat not only Chagas' disease but also other neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS042960-01
Application #
6438541
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Kerza-Kwiatecki, a P
Project Start
2001-12-15
Project End
2004-11-30
Budget Start
2001-12-15
Budget End
2002-11-30
Support Year
1
Fiscal Year
2002
Total Cost
$324,900
Indirect Cost
Name
Tufts University
Department
Pathology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111
Salvador, Ryan; Aridgides, Daniel; PereiraPerrin, Mercio (2014) Parasite-derived neurotrophic factor/trans-sialidase of Trypanosoma cruzi links neurotrophic signaling to cardiac innate immune response. Infect Immun 82:3687-96
Aridgides, Daniel; Salvador, Ryan; PereiraPerrin, Mercio (2013) Trypanosoma cruzi coaxes cardiac fibroblasts into preventing cardiomyocyte death by activating nerve growth factor receptor TrkA. PLoS One 8:e57450
Aridgides, Daniel; Salvador, Ryan; PereiraPerrin, Mercio (2013) Trypanosoma cruzi highjacks TrkC to enter cardiomyocytes and cardiac fibroblasts while exploiting TrkA for cardioprotection against oxidative stress. Cell Microbiol 15:1357-66
Chuenkova, Marina V; Pereiraperrin, Mercio (2010) Trypanosoma cruzi-Derived Neurotrophic Factor: Role in Neural Repair and Neuroprotection. J Neuroparasitology 1:55-60
Lu, B; Luquetti, A O; Rassi, A et al. (2010) Autoantibodies to neurotrophic receptors TrkA, TrkB and TrkC in patients with acute Chagas' disease. Scand J Immunol 71:220-5
Chuenkova, Marina V; PereiraPerrin, Mercio (2009) Trypanosoma cruzi targets Akt in host cells as an intracellular antiapoptotic strategy. Sci Signal 2:ra74
Weinkauf, Craig; Pereiraperrin, Mercio (2009) Trypanosoma cruzi promotes neuronal and glial cell survival through the neurotrophic receptor TrkC. Infect Immun 77:1368-75
Lu, B; Petrola, Z; Luquetti, A O et al. (2008) Auto-antibodies to receptor tyrosine kinases TrkA, TrkB and TrkC in patients with chronic Chagas'disease. Scand J Immunol 67:603-9
Akpan, Nsikan; Caradonna, Kacey; Chuenkova, Marina V et al. (2008) Chagas'disease parasite-derived neurotrophic factor activates cholinergic gene expression in neuronal PC12 cells. Brain Res 1217:195-202
Lu, Bo; Alroy, Joseph; Luquetti, Alejandro O et al. (2008) Human autoantibodies specific for neurotrophin receptors TrkA, TrkB, and TrkC protect against lethal Trypanosoma cruzi infection in mice. Am J Pathol 173:1406-14

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