Cutting edge: small molecule CD40 ligand mimetics promote control of parasitemia and enhance T cells producing IFN-gamma during experimental Trypanosoma cruzi infection.
Host resistance to Trypanosoma cruzi infection depends on a type 1 response characterized by a strong production of IL-12 and IFN-gamma. Amplifying this response through CD40 triggering results in control of parasitemia. Two newly synthesized molecules (<3 kDa) mimicking trimeric CD40L (mini CD40Ls(-1) and (-2)) bind to CD40, activate murine dendritic cells, and elicit IL-12 production. Wild-type but not CD40 knockout mice exhibited a sharp decrease of parasitemia and mortality when inoculated with T. cruzi mixed with miniCD40Ls. Moreover, the immunosuppression induced by T. cruzi infection was impaired in mice treated with miniCD40Ls, as shown by proliferation of splenic lymphocytes, percentage of CD8(+) T cells, and IFN-gamma production. Mice surviving T. cruzi infection in the presence of miniCD40L(-1) were immunized against a challenge infection. Our results indicate that CD40L mimetics are effective in vivo and promote the control of T. cruzi infection by overcoming the immunosuppression usually induced by the parasites.
Habib
Mohammed
M
Laboratoire d'Immunologie Expérimentale, Université Libre de Bruxelles, Brussels, Belgium.
Noval Rivas
Magali
M
Chamekh
Mustapha
M
Wieckowski
Sébastien
S
Sun
Weimin
W
Bianco
Alberto
A
Trouche
Nathalie
N
Chaloin
Olivier
O
Dumortier
Hélène
H
Goldman
Michel
M
Guichard
Gilles
G
Fournel
Sylvie
S
Vray
Bernard
B
D000818:Animals; D019013:CD40 Antigens / Q000378:metabolism / Q000502:physiology; D023201:CD40 Ligand / Q000138:chemical synthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D014355:Chagas Disease / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D007371:Interferon-gamma / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018716:Molecular Mimicry / Q000276:immunology*; D018512:Parasitemia / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D014349:Trypanosoma cruzi / Q000276:immunology
D019013:CD40 Antigens; D023201:CD40 Ligand; D007371:Interferon-gamma