The role of TrkA in Trypanosoma cruzi invasion

• Main Author: de Melo Jorge, Milena
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2008
• Subjects: Immunology; Parasitology
• ISBN: 9780549536635; 0549536639

Trypanosoma cruzi, the etiological agent of Chagas' disease, is an obligate intracellular parasite that invades several cell types by unknown mechanisms. Here we show that T. cruzi reacts with cells through the recognition of tyrosine kinase receptor TrkA, which normally binds to nerve growth factor in the regulation of neuronal development and repair. T. cruzi, via the surface protein PDNF, binds to TrkA and activates downstream signaling pathways. Deletion of the TrkA gene from neuronal cells reduces parasite adhesion and invasion. Transfecting full-length functional TrkA, but not kinase deficient TrkA, restores wild-type infection potential. Neutralizing kinase activity with pharmacological agents abrogates TrkA-depedent T. cruzi invasion. Most interestingly, soluble TrkA and TrkA-blocking agents reduce infection in cellular and animal models of acute Chagas' disease. As a likely molecular mechanism for T. cruzi activation of TrkA, we found that PDNF has a 24 amino-acid sequence, PL4, analogous to a NGF domain that contains TrkA-binding specificity motifs β-hairpin loop-4 and Gln-Ala-Ala. Synthetic PL4 reproduces full-length PDNF and NGF in inhibiting TrkA binding to live T. cruzi, promoting cell survival, and blocking cell invasion and T. cruzi-induced cell survival. Remarkably, these actions are lost by mutating the Gln-Ala-Ala analog in PL4. In conclusion, we show that TrkA, a receptor commonly associated with neuronal survival and protection, may serve as a mechanism for T. cruzi to invade cells and, therefore, as a determing factor for the pathogenesis of Chagas' disease. We also find that PDNF mimics a NGF-structural motif that binds and activates TrkA, which could be useful in the development of anti-adhesion therapy for Chagas' disease. Taken together, our findings suggest that, while infecting the nervous system, T. cruzi exploits TrkA to promote concurrent cell survival and invasion in an attempt to reduce host tissue damage.