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.
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