科研之友
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摘要
Background Protozoan parasites from the genus Leishmania cause broad clinical manifestations known as leishmaniases, which affect millions of people worldwide. Cutaneous leishmaniasis (CL), caused by L. major, is one the most common forms of the disease in the Old World. There is no preventive or therapeutic human vaccine available for L. major CL and existing drug treatments are expensive, have toxic side effects, and resistant parasite strains have been reported. Hence, further therapeutic interventions against the disease are necessary. Terminal, non-reducing, and linear alpha-galactopyranosyl (alpha-Gal) epitopes are abundantly found on the plasma membrane glycolipids of L. major known as glycoinositolphospholipids. The absence of these alpha-Gal epitopes in human cells makes these glycans highly immunogenic and thus potential targets for vaccine development against CL. Methodology/Principal findings Here, we evaluated three neoglycoproteins (NGPs), containing synthetic alpha-Gal epitopes covalently attached to bovine serum albumin (BSA), as vaccine candidates against L. major, using alpha 1,3-galactosyltransferase-knockout (alpha 1,3GalT-KO) mice. These transgenic mice, similarly to humans, do not express nonreducing, linear alpha-Gal epitopes in their cells and are, therefore, capable of producing high levels of anti-alpha-Gal antibodies. We observed that Gal alpha(1,6)Gal beta-BSA (NGP5B), but not Gal alpha(1,4)Gal beta-BSA (NGP12B) or Gal alpha(1,3), Gal alpha-BSA (NGP17B), was able to significantly reduce the size of footpad lesions by 96/. in comparison to control groups. Furthermore, we observed a robust humoral and cellular immune response with production of high levels of protective lytic anti-alpha-Gal antibodies and induction of Thl cytokines. Conclusions/Significance We propose that NGP5B is an attractive candidate for the study of potential synthetic alpha-Galneoglycoprotein-based vaccines against L. major infection. Author summary Despite a worldwide prevalence, cutaneous leishmaniasis (CL) remains largely neglected with no prophylactic or therapeutic vaccine available. In the Old World, CL is mainly caused by either Leishmania major or L. tropica parasites, which produce localized cutaneous ulcers, often leading to scarring and social stigma. Currently, the disease has reached hyperendemicity levels in the Middle East due to conflict and human displacement. Furthermore, the first choice of treatment in that region continues to be pentavalent antimonials, which are costly and highly toxic, sand current vector control measures alone are not sufficient to stop disease transmission. Hence, a vaccine against CL would be very beneficial. Previous studies have demonstrated that sugars are promising vaccine candidates against leishmaniasis, since most parasite species have a cell surface coat composed of immunogenic sugars, including linear alpha-galactopyranosyl (alpha-Gal) epitopes, which are absent in humans. Here, we have developed an alpha-Gal-based vaccine candidate, named NGP5B. When tested in transgenic mice which like humans lack alpha-Gal epitopes in their cells, NGP5B was able to induce a significant partial protection against L. major infection, by significantly reducing mouse footpad lesions and parasite burden. Altogether, we propose NGP5B as a promising preventive vaccine for CL caused by L. major.
- 出版日期2017-10
- 单位MIT
