☆ 4.6 Article

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

NPJ VACCINES (2019)

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NPJ VACCINES

卷 4, 期 -, 页码 -

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DOI: 10.1038/s41541-019-0107-7

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Immunology Medicine, Research & Experimental

资金

National Institute on Minority Health and Health Disparities (NIMHD) [2G12MD007592]
DHHS/NCI Cancer Center Support Grant (CCSG) [P30 CA16672]
NIH [1R21AI115451]
UTEP College of Science Multidisciplinary Pilot Projects and Collaborations Grant
Dr. Keelung Hong Graduate Research Fellowship
UTEP Dodson Research Grant
Diana Natalicio Doctoral Dissertation Fellowship at UTEP (NIGMS) [R25GM069621-11]
RISE Scholars Program at UTEP (NIGMS) [R25GM069621-11]
Frank B. Cotton Trust Scholarship, from UTEP Graduate School

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摘要

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 alpha-galactopyranosyl (alpha-Gal)-containing glycotopes that are entirely absent in humans. The immunodominant tGPI-mucin alpha-Gal glycotope, the trisaccharide Gal alpha 1,3Gal beta 1,4GlcNAc (Gal alpha 3LN), elicits high levels of protective T. cruzi-specific anti-alpha-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 alpha 3LN, covalently linked to a carrier protein (human serum albumin (HSA)), as a prophylactic vaccine candidate in the acute model of ChD, using the alpha 1,3-galactosyltransferase-knockout (alpha 1,3GalT-KO) mouse, which mimics the human immunoresponse to alpha-Gal glycotopes. Animals vaccinated with Gal alpha 3LN-HSA were fully protected against lethal T. cruzi challenge by inducing a strong anti-alpha-Gal antibody-mediated humoral response. Furthermore, Gal alpha 3LN-HSA-vaccinated alpha 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 alpha-Gal-based glycovaccine for experimental acute Chagas disease.

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