The Trypanosoma cruzi Tc52-released protein induces human dendritic cell maturation, signals via Toll-like receptor 2, and confers protection against lethal infection.
The intracellular protozoan parasite Trypanosoma cruzi is the etiological agent of Chagas disease. We have recently identified a T. cruzi-released protein related to thiol-disulfide oxidoreductase family, called Tc52, which is crucial for parasite survival and virulence. In vitro, Tc52 in combination with IFN-gamma activates human macrophages. In vivo, active immunization with Tc52 relieves the immunosuppression associated to acute infection and elicits a specific immune response. As dendritic cells (DC) have a central role in the initiation of immune responses, we investigated whether Tc52 may modulate DC activity. We show that Tc52 induces human DC maturation. Tc52-treated immature DC acquire CD83 and CD86 expression, produce inflammatory chemokines (IL-8, monocyte chemoattractant protein-1, and macrophage-inflammatory protein-1 alpha), and present potent costimulatory properties. Tc52 binds to DC by a mechanism with the characteristics of a saturable receptor system and signals via Toll-like receptor 2. While Tc52-mediated signaling involves its reduced glutathione-binding site, another portion of the molecule is involved in Tc52 binding to DC. Finally, we report that immunization with Tc52 protects mice in vivo against lethal infection with T. cruzi. Together these data evidence complex molecular interactions between the T. cruzi-derived molecule, Tc52, and DC, and suggest that Tc52 and related class of proteins might represent a new type of pathogen-associated molecular patterns. Moreover, the immune protection data suggest that Tc52 is among candidate molecules that may be used to design an optimal multicomponent vaccine to control T. cruzi infection.
Ouaissi
Ali
A
Institut de Recherche pour le Développement UR 008, Montpellier, France. ali.ouaissi@montp.inserm.fr
Guilvard
Eliane
E
Delneste
Yves
Y
Caron
Gersende
G
Magistrelli
Giovanni
G
Herbault
Nathalie
N
Thieblemont
Nathalie
N
Jeannin
Pascale
P
D000818:Animals; D001665:Binding Sites / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D014355:Chagas Disease / Q000201:enzymology / Q000276:immunology / Q000401:mortality* / Q000517:prevention & control*; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D029721:Drosophila Proteins; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding / Q000276:immunology; D011490:Protein Disulfide Reductase (Glutathione) / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015800:Protozoan Proteins / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D016052:Protozoan Vaccines / Q000008:administration & dosage / Q000276:immunology; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014349:Trypanosoma cruzi / Q000201:enzymology* / Q000276:immunology
C097550:52-kDa protein, Trypanosoma cruzi; D029721:Drosophila Proteins; D008562:Membrane Glycoproteins; D015800:Protozoan Proteins; D016052:Protozoan Vaccines; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D011490:Protein Disulfide Reductase (Glutathione); D005978:Glutathione