Trypanosoma cruzi is a protozoan parasite that causes Chagas disease in Central America. Over 11 million people are infected, and up to 50,000 die each year due to complications during the chronic stage of the disease. No effective drugs exist to treat chronic Chagas disease, and no vaccination is available to date. The long-term goal of this pilot project is to obtain critical exploratory vaccine/immune response data that will ultimately lead to an effective vaccine that provides full protection to immunized individuals. The P.I.'s approach differs fundamentally from others'attempts to develop a vaccine for Chagas disease by the idea of incorporating parasitic cell surface carbohydrate epitopes into fully synthetic vaccines. The glycocalix of trypomastigotes, the infective forms of the parasite, contains large amounts of structurally heterogeneous glycans with terminal 1-galactosyl moieties, which are foreign to humans. Furthermore, the sera of Chagasic patients contain antibodies, known as anti-1-Gal, with a unique function, i.e. they cause lysis of trypomastigotes by recognition of 1-galactosyl epitopes. Therefore, it is hypothesized that the trypomastigotes'1-galactosides are extremely immunogenic B-cell epitopes that elicit highly effective lytic antibodies. It is further hypothesized that a fully effective vaccine should elicit both, lytic antibodies as well as cytotoxic T-cells. Therefore, two types of synthetic vaccine candidates that contain different epitopes will be generated and used in combination. Five small synthetic oligosaccharide haptens with terminal 1-galactosides will be synthesized and conjugated to carrier proteins. The neoglycoproteins will be used for initial screening immunization of 1-1,3- galactosyltransferase knockout (11,3GalT-KO) mice, which in contrast to wild-type counterparts, are responsive to 1-galactosides, and are therefore a good model for humans. The sera of immunized animals will be tested for their ability to lyse trypomastigotes in vitro. The 1-galactoside epitopes that are capable of evoking such an immune response will then be used to generate potentially superior vaccines by incorporating them into fully synthetic glycolipopeptides. These conjugates will be designed to contain: (a) one or more 1- galactoside(s) as B-cell epitopes;(b) a CD4+ epitope for the activation of helper T-cells;and (c) a lipid moiety as an adjuvant that targets Toll-like receptors of dendritic cells. Another type of conjugate will consist of (a) a lipid;and (b) one or two Trypanosoma cruzi specific CD8+ T-cell epitopes to elicit cytotoxic T-cells. The humoral and cellular immune responses of mice to these potential vaccines will be studied. If successful, this exploratory research project will create the molecular basis for the development of the first effective human vaccine for Chagas disease, which would have a tremendous impact on public health, and may save thousands of lives in Central America. In addition, the described concept of fully synthetic vaccines may have a much broader relevance for translational research, as it may be applicable to other endemic parasitic and infectious diseases.
Chagas disease is a life-threatening disease in Central America that is transmitted by the blood- sucking triatome bug, and is caused by a unicellular parasite, Trypanosoma cruzi, that expresses certain immunogenic 1-galactosides on its cell surface. Our goal is to construct fully synthetic glycoconjugates that resemble the cell surface of the parasite, and test them in immunization studies in mice. The results of this research could lead to a vaccine which would have a tremendous impact on public health, not only by saving thousands of lives in Central America, but also by protecting individuals under risk in the U.S.
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