The Chagas' Disease Parasite Trypanosoma cruzi Exploits Nerve Growth Factor Receptor TrkA to Infect Mammalian Hosts

Abstract

Trypanosoma cruzi, the agent of Chagas' disease, is an obligate intracellular parasite that invades various organs including several cell types in the nervous system that express the Trk receptor tyrosine kinase. Activation of Trk is a major cell-survival and repair mechanism, and parasites could use Trks to invade cells as a strategy to protect their habitat and prolong parasitism of vertebrate hosts. We show that T. cruzi binds to TrkA specifically and activates TrkA-dependent survival mechanisms. This interaction facilitates parasite adherence and promotes efficient invasion of neuronal, epithelial, and phagocytic cells via a process that requires TrkA kinase activity. Diffusible TrkA and TrkA-blocking agents neutralized infection in cellular and animal models of acute Chagas' disease, suggesting cellular receptors as therapeutic targets against parasitic diseases. Thus, TrkA, the nerve growth factor receptor commonly associated with neural survival and protection, may also underlie clinical progression of an important human parasitic disease.

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

“…PDNF activation of differentiation and survival of cells of the nervous system, through the recognition of TrkC, widens the scope for the possible role that T. cruzi plays in helping repair infected nervous tissues (2,10,18). This would be broadened even further by T. cruzi activation of TrkB, as reported, without the use of T. cruzi, with a bacterially expressed truncated form of trans-sialidase (49).…”

“…cruzi binds to TrkC. To determine whether T. cruzi binds TrkB and/or TrkC, we followed a procedure similar to the one used previously to study T. cruzi-TrkA interactions (18). First, parasites were incubated with Fc chimera of the extracellular domain (ECD) of TrkB and TrkC receptors, hereafter called TrkB and TrkC unless stated otherwise.…”

Neurotrophin Receptor TrkC Is an Entry Receptor for Trypanosoma cruzi in Neural, Glial, and Epithelial Cells

“…Recently, it was shown in our lab that T. cruzi uses the tyrosine receptor kinase TrkA to invade neural cells (12). However, TrkA expression in the nervous system is restricted to a subset of neurons, particularly in the CNS, where it is located only in the forebrain (17,23).…”

Molecular analysis of early host cell infection by Trypanosoma cruzi

“…Its was also reported that T. cruzi infects PC12 cells by activating TrKA and that injection of an inhibitor of TrkA auto phosphorylation, or TrKA into mice attenuates T. cruzi infection (156). It was suggested that this activation also facilitates neuron survival (154).…”