385 Anti-α-Galactopyranosyl (anti-Gal) Antibodies Protect α1,3-Galactosyltransferase-Knockout Mice against Trypanosoma Cruzi Infection

Friday, November 6, 2009: 3:50 PM
Angus (Camino Real Hotel)
Alexandre F. Marques , Dept. of Biological Sciences, The Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX
Lilian L. Nohara , Dept. of Biological Sciences, The Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX
Ernesto S. Nakayasu , Dept. of Biological Sciences, The Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX
Igor C. Almeida , Dept. of Biological Sciences, The Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX
Chagas disease (CD), caused by the protozoon Trypanosoma cruzi, affects millions of people in Latin America and, lately, threats the U.S. and Europe. There is no effective chemotherapy or a human vaccine for CD. The involvement of antibodies in the resistance against T. cruzi remains unclear. Nevertheless, high titers of lytic anti-α-galactopyranosyl antibodies (anti-Gal Abs), elicited against highly immunogenic α-Gal epitopes expressed by T. cruzi glycoconjugates are ubiquitously found in CD patients. Therefore, α-Gal epitopes have clinical potential in the generation of an effective human vaccine. Here we evaluate the role of anti-Gal Abs during the acute phase of experimental CD using C57Bl/6 wild-type (WT) and α1,3-galactosyltransferase gene-knockout (α1,3-GalT-KO) mice. Contrary to WT controls, α1,3-GalT-KO mice infected with 1e4 T. cruzi trypomastigote forms showed high titers of anti-Gal Abs. Consequently, these mice had lower parasitemia and much higher (80%) survival rate as compared to WT controls in the fourth week post-infection. Also, in contrast to WT controls, α1,3-GalT-KO mice passively immunized with murine anti-Gal-containing anti-serum one hour prior to lethal challenge (1e5 trypomastigotes) survived parasite challenge up to 18 weeks post-infection. In addition, α1,3-GalT-KO mice showed much higher proinflammatory (IL-12, IFN-γ) and lower anti-inflammatory (IL-10, IL-4) cytokine levels than WT controls. Taken together, our results demonstrate that the lytic, protective anti-Gal Abs and proinflammatory immune response produced by T. cruzi-infected α1,3-GalT-KO mice can contribute to the effective parasite control in the acute phase of experimental CD. Immunization experiments using the Galα1,3Galβ1,4GlcNac-BSA neoglycoprotein as immunogen and the synthetic trypomastigote-derived glycosylphosphatidylinositol (stGPI) as adjuvant are underway. Funding: NIH grants S06GM008012 and 5G12RR008124.