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A prophylactic ?-Gal-based glycovaccine effectively protects against murine acute Chagas disease.

ABSTRACT: Chagas disease (ChD), caused by the hemoflagellate parasite Trypanosoma cruzi, affects six to seven million people in Latin America. Lately, it has become an emerging public health concern in nonendemic regions such as North America and Europe. There is no prophylactic or therapeutic vaccine as yet, and current chemotherapy is rather toxic and has limited efficacy in the chronic phase of the disease. The parasite surface is heavily coated by glycoproteins such as glycosylphosphatidylinositol (GPI)-anchored mucins (tGPI-mucins), which display highly immunogenic terminal nonreducing ?-galactopyranosyl (?-Gal)-containing glycotopes that are entirely absent in humans. The immunodominant tGPI-mucin ?-Gal glycotope, the trisaccharide Gal?1,3Gal?1,4GlcNAc (Gal?3LN), elicits high levels of protective T. cruzi-specific anti-?-Gal antibodies in ChD patients in both the acute and chronic phases. Although glycoconjugates are the major parasite glycocalyx antigens, they remain completely unexplored as potential ChD vaccine candidates. Here we investigate the efficacy of the T. cruzi immunodominant glycotope Gal?3LN, covalently linked to a carrier protein (human serum albumin (HSA)), as a prophylactic vaccine candidate in the acute model of ChD, using the ?1,3-galactosyltransferase-knockout (?1,3GalT-KO) mouse, which mimics the human immunoresponse to ?-Gal glycotopes. Animals vaccinated with Gal?3LN-HSA were fully protected against lethal T. cruzi challenge by inducing a strong anti-?-Gal antibody-mediated humoral response. Furthermore, Gal?3LN-HSA-vaccinated ?1,3GalT-KO mice exhibited significant reduction (91.7-99.9%) in parasite load in all tissues analyzed, cardiac inflammation, myocyte necrosis, and T cell infiltration. This is a proof-of-concept study to demonstrate the efficacy of a prophylactic ?-Gal-based glycovaccine for experimental acute Chagas disease.

SUBMITTER: Portillo S

PROVIDER: S-EPMC6430786 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A prophylactic α-Gal-based glycovaccine effectively protects against murine acute Chagas disease.

Portillo Susana S Zepeda Brenda G BG Iniguez Eva E Olivas Janet J JJ Karimi Nasim H NH Moreira Otacilio C OC Marques Alexandre F AF Michael Katja K Maldonado Rosa A RA Almeida Igor C IC

NPJ vaccines 20190322

Chagas disease (ChD), caused by the hemoflagellate parasite <i>Trypanosoma cruzi</i>, affects six to seven million people in Latin America. Lately, it has become an emerging public health concern in nonendemic regions such as North America and Europe. There is no prophylactic or therapeutic vaccine as yet, and current chemotherapy is rather toxic and has limited efficacy in the chronic phase of the disease. The parasite surface is heavily coated by glycoproteins such as glycosylphosphatidylinosi ...[more]

PMID: 30911415

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Project description:The protozoan parasite, Trypanosoma cruzi, the etiologic agent of Chagas disease (ChD), has a cell surface covered by immunogenic glycoconjugates. One of the immunodominant glycotopes, the trisaccharide Gal?(1,3)Gal?(1,4)GlcNAc?, is expressed on glycosylphosphatidylinositol-anchored mucins of the infective trypomastigote stage of T. cruzi and triggers high levels of protective anti-?-Gal antibodies (Abs) in infected individuals. Here, we have efficiently synthesized the mercaptopropyl glycoside of that glycotope and conjugated it to maleimide-derivatized bovine serum albumin (BSA). Chemiluminescent-enzyme-linked immunosorbent assay revealed that Gal?(1,3)Gal?(1,4)GlcNAc?-BSA is recognized by purified anti-?-Gal Abs from chronic ChD patients ?230-fold more strongly than by anti-?-Gal Abs from sera of healthy individuals (NHS anti-?-Gal). Similarly, the pooled sera of chronic Chagas disease patients (ChHSP) recognized Gal?(1,3)Gal?(1,4)GlcNAc? ?20-fold more strongly than pooled NHS. In contrast, the underlying disaccharide Gal?(1,4)GlcNAc? and the monosaccharide GlcNAc? or GlcNAc? conjugated to BSA are poorly or not recognized by purified anti-?-Gal Abs or sera from Chagasic patients or healthy individuals. Our results highlight the importance of the terminal Gal? moiety for recognition by Ch anti-?-Gal Abs and the lack of Abs against nonself Gal?(1,4)GlcNAc? and GlcNAc? glycotopes. The substantial difference in binding of Ch vs. NHS anti-?-Gal Abs to Gal?(1,3)Gal?(1,4)GlcNAc?-BSA suggests that this neoglycoprotein (NGP) might be suitable for experimental vaccination. To this end, the Gal?(1,3)Gal?(1,4)GlcNAc?-BSA NGP was then used to immunize ?1,3-galactosyltransferase-knockout mice, which produced antibody titers 40-fold higher as compared with pre-immunization titers. Taken together, our results indicate that the synthetic Gal?(1,3)Gal?(1,4)GlcNAc? glycotope coupled to a carrier protein could be a potential diagnostic and vaccine candidate for ChD.

Dataset Information

A prophylactic ?-Gal-based glycovaccine effectively protects against murine acute Chagas disease.

Publications

A prophylactic α-Gal-based glycovaccine effectively protects against murine acute Chagas disease.

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