Chagas disease, caused by the protozoan Trypanosoma cruzi, progresses through 3 stages: 1) acute disease, characterized by robust parasite growth, immunological disturbances, and peripheral neural degeneration; 2) indeterminate phase, asymptomatic and featuring extensive regeneration of neurons; and 3) chronic phase, characterized by immunological alterations and pronounced degeneration of neurons in the heart and GI tract. Most patients remain asymptomatic and with signs of neuronal regeneration for decades, but for enigmatic reasons, some (<10 percent) undergo extensive degeneration of neurons (along with immunological disturbances) to progress to the fatal chronic disease. Recent studies may provide insights into the molecular basis of neuronal changes in Chagas disease. Picomolar levels of the T. cruzi trans-sialidase (TS) were found to protect several types of neuronal cells from undergoing apoptotic death. What's more, TS synergized with two human neurotrophic cytokines, ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF), to promote neuronal survival. Therefore, the possibility exists that neuronal regeneration in Chagas disease results from the collaboration of TS with CNTF or LIF. In addition, and most interesting, because about 2.5 percent and 25 percent of normal people are homozygous and heterozygous, respectively, for a null mutation in the CNTF gene, the possibility exists that individuals bearing mutation of this neurotrophic cytokine are more prone to develop extensive degeneration of neurons if infected with T. cruzi and thus to progress to chronic Chagas' disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040574-03
Application #
6540346
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Nunn, Michael
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
3
Fiscal Year
2002
Total Cost
$369,000
Indirect Cost
Name
Tufts University
Department
Pathology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02111
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Lu, Bo; PereiraPerrin, Mercio (2008) A novel immunoprecipitation strategy identifies a unique functional mimic of the glial cell line-derived neurotrophic factor family ligands in the pathogen Trypanosoma cruzi. Infect Immun 76:3530-8

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