Document Detail


Neurotrophin receptor TrkC is an entry receptor for Trypanosoma cruzi in neural, glial, and epithelial cells.
MedLine Citation:
PMID:  21788388     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Trypanosoma cruzi, the agent of Chagas' disease, infects a variety of mammalian cells in a process that includes multiple cycles of intracellular division and differentiation starting with host receptor recognition by a parasite ligand(s). Earlier work in our laboratory showed that the neurotrophin-3 (NT-3) receptor TrkC is activated by T. cruzi surface trans-sialidase, also known as parasite-derived neurotrophic factor (PDNF). However, it has remained unclear whether TrkC is used by T. cruzi to enter host cells. Here, we show that a neuronal cell line (PC12-NNR5) relatively resistant to T. cruzi became highly susceptible to infection when overexpressing human TrkC but not human TrkB. Furthermore, trkC transfection conferred an ∼3.0-fold intracellular growth advantage. Sialylation-deficient Chinese hamster ovarian (CHO) epithelial cell lines Lec1 and Lec2 also became much more permissive to T. cruzi after transfection with the trkC gene. Additionally, NT-3 specifically blocked T. cruzi infection of the TrkC-NNR5 transfectants and of naturally permissive TrkC-bearing Schwann cells and astrocytes, as did recombinant PDNF. Two specific inhibitors of Trk autophosphorylation (K252a and AG879) and inhibitors of Trk-induced MAPK/Erk (U0126) and Akt kinase (LY294002) signaling, but not an inhibitor of insulin-like growth factor 1 receptor, abrogated TrkC-mediated cell invasion. Antibody to TrkC blocked T. cruzi infection of the TrkC-NNR5 transfectants and of cells that naturally express TrkC. The TrkC antibody also significantly and specifically reduced cutaneous infection in a mouse model of acute Chagas' disease. TrkC is ubiquitously expressed in the peripheral and central nervous systems, and in nonneural cells infected by T. cruzi, including cardiac and gastrointestinal muscle cells. Thus, TrkC is implicated as a functional PDNF receptor in cell entry, independently of sialic acid recognition, mediating broad T. cruzi infection both in vitro and in vivo.
Authors:
Craig Weinkauf; Ryan Salvador; Mercio Pereiraperrin
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Publication Detail:
Type:  Journal Article     Date:  2011-07-25
Journal Detail:
Title:  Infection and immunity     Volume:  79     ISSN:  1098-5522     ISO Abbreviation:  Infect. Immun.     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-09-22     Completed Date:  2011-11-15     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  0246127     Medline TA:  Infect Immun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4081-7     Citation Subset:  IM    
Affiliation:
Graduate Program in Immunology, Sackler School of Graduate Biomedical Sciences, Department of Pathology, Tufts University School of Medicine, Boston, MA 02111, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Astrocytes / parasitology
CHO Cells
Cell Line
Cells, Cultured
Chagas Disease / parasitology,  pathology
Cricetinae
Cricetulus
Epithelial Cells / parasitology*
Female
Glycoproteins / metabolism
Humans
Male
Mice
Mice, Inbred C57BL
Neuraminidase / metabolism
Neuroglia / parasitology*
Neurons / parasitology*
Receptor, trkC / genetics,  metabolism*
Trypanosoma cruzi / metabolism,  pathogenicity*
Chemical
Reg. No./Substance:
0/Glycoproteins; EC 2.7.10.1/Receptor, trkC; EC 3.2.1.-/trans-sialidase; EC 3.2.1.18/Neuraminidase
Comments/Corrections

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