Document Detail


Trypanosoma cruzi highjacks TrkC to enter cardiomyocytes and cardiac fibroblasts while exploiting TrkA for cardioprotection against oxidative stress.
MedLine Citation:
PMID:  23414299     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Chronic Chagas cardiomyopathy (CCC), caused by the obligate intracellular protozoan parasite Trypanosoma cruzi, is a major cause of morbidity and mortality in Latin America. 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 cardiac cell 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.
Authors:
Daniel Aridgides; Ryan Salvador; Mercio PereiraPerrin
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Publication Detail:
Type:  Comparative Study; Journal Article     Date:  2013-03-14
Journal Detail:
Title:  Cellular microbiology     Volume:  15     ISSN:  1462-5822     ISO Abbreviation:  Cell. Microbiol.     Publication Date:  2013 Aug 
Date Detail:
Created Date:  2013-07-15     Completed Date:  2014-01-30     Revised Date:  2014-05-12    
Medline Journal Info:
Nlm Unique ID:  100883691     Medline TA:  Cell Microbiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1357-66     Citation Subset:  IM    
Copyright Information:
© 2013 John Wiley & Sons Ltd.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cells, Cultured
Chagas Cardiomyopathy
Disease Models, Animal
Fibroblasts / parasitology*,  pathology,  physiology
Glycoproteins / physiology
Host-Parasite Interactions / physiology
Mice
Mice, Inbred C57BL
Myocytes, Cardiac / parasitology*,  pathology,  physiology
Neuraminidase / physiology
Oxidative Stress / physiology*
RNA, Small Interfering / pharmacology
Receptor, trkA / physiology*
Receptor, trkC / antagonists & inhibitors,  drug effects,  physiology*
Trypanosoma cruzi / pathogenicity*,  physiology
Grant Support
ID/Acronym/Agency:
R01 NS040574/NS/NINDS NIH HHS; R01 NS042960/NS/NINDS NIH HHS; R56 AI097378/AI/NIAID NIH HHS; T32 AI007077/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Glycoproteins; 0/RNA, Small Interfering; EC 2.7.10.1/Receptor, trkA; EC 2.7.10.1/Receptor, trkC; EC 3.2.1.-/trans-sialidase; EC 3.2.1.18/Neuraminidase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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