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 #
5R01NS040574-05
Application #
6751604
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
2004-07-01
Budget End
2005-06-30
Support Year
5
Fiscal Year
2004
Total Cost
$369,000
Indirect Cost
Name
Tufts University
Department
Pathology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
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
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
Caradonna, Kacey; Pereiraperrin, Mercio (2009) Preferential brain homing following intranasal administration of Trypanosoma cruzi. Infect Immun 77:1349-56
Correia, J W; Freitas, M V; Queiroz, J A et al. (2009) Interleukin-6 blood levels in sensitive and multiresistant tuberculosis. Infection 37:138-41
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; 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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