Trypanosoma cruziPromotes Neuronal and Glial Cell Survival through the Neurotrophic Receptor TrkC

Abstract

Trypanosoma cruzi, the agent of Chagas' disease, promotes neuron survival through receptor tyrosine kinase TrkA and glycosylphosphatidylinositol-anchored glial cell-derived family ligand receptors (GFRα). However, these receptors are expressed by only a subset of neurons and at low levels or not at all in glial cells. Thus,T. cruzimight exploit an additional neurotrophic receptor(s) to maximize host-parasite equilibrium in the nervous system. We show here thatT. cruzibinds TrkC, a neurotrophic receptor expressed by glial cells and many types of neurons, and that the binding is specifically inhibited by neurotrophin-3, the natural TrkC ligand. Coimmunoprecipitation and competition assays show that thetrans-sialidase/parasite-derived neurotrophic factor (PDNF), previously identified as a TrkA ligand, mediates theT. cruzi-TrkC interaction. PDNF promotes TrkC-dependent mitogen-activated protein kinase signaling, neurite outgrowth, and survival of genetically engineered PC12 neuronal cells and glial Schwann cells in a TrkC-dependent manner. Thus, TrkC is a new neurotrophic receptor thatT. cruziengages to promote the survival of neuronal and glial cells. The results raise the possibility thatT. cruzirecognition of TrkC underlies regenerative events in nervous tissues of patients with Chagas' disease.