Open AccessT rypanosoma cruzi highjacks TrkC to enter cardiomyocytes and cardiac fibroblasts while exploiting TrkA for cardioprotection against oxidative stress
Author(s) -
Aridgides Daniel,
Salvador Ryan,
PereiraPerrin Mercio
Publication year - 2013
Publication title -
cellular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.542
H-Index - 138
eISSN - 1462-5822
pISSN - 1462-5814
DOI - 10.1111/cmi.12119
Subject(s) - biology , tropomyosin receptor kinase c , tropomyosin receptor kinase a , microbiology and biotechnology , low affinity nerve growth factor receptor , trypanosoma cruzi , neurotrophin , tropomyosin receptor kinase b , receptor , platelet derived growth factor receptor , biochemistry , neurotrophic factors , growth factor , parasite hosting , world wide web , computer science
Summary Chronic C hagas cardiomyopathy ( CCC ), caused by the obligate intracellular protozoan parasite T rypanosoma cruzi , is a major cause of morbidity and mortality in L atin A merica. CCC begins when T . cruzi enters cardiac cells for intracellular multiplication and differentiation, a process that starts with recognition of host–cell entry receptors. However, the nature of these surface molecules and corresponding parasite counter‐receptor(s) is poorly understood. Here we show that antibodies against neurotrophin ( NT ) receptor TrkC , but not against family members TrkA and TrkB , prevent T . cruzi from invading primary cultures of cardiomyocytes and cardiac fibroblasts. Invasion is also selectively blocked by the TrkC ligand NT ‐3, and by antagonists of Trk autophosphorylation and downstream signalling. Therefore, these results indicate that T . cruzi gets inside cardiomyocytes and cardiac fibroblasts by activating TrkC preferentially over TrkA . Accordingly, short hairpin RNA interference of TrkC ( shTrkC ), but not TrkA , selectively prevents T . cruzi from entering cardiac cells. Additionally, T . cruzi parasite‐derived neurotrophic factor ( PDNF )/ trans‐ sialidase, a TrkC ‐binding protein, but not family member gp85, blocks entry dose‐dependently, underscoring the specificity of PDNF as TrkC counter‐receptor in cardiaccell invasion. In contrast to invasion, competitive and shRNA inhibition studies demonstrate that T . cruzi – PDNF recognition of TrkA , but not TrkC on primary cardiomyocytes and the cardiomyocyte cell line H9c2 protects the cells against oxidative stress. Thus, this study shows that T . cruzi via PDNF favours neurotrophin receptor TrkC for cardiac cell entry and TrkA for cardiomyocyte protection against oxidative stress, and suggests a new therapeutic opportunity in PDNF and/or fragments thereof for CCC therapy as entry inhibitors and/or cardioprotection agonists.