GLYCOSYLATION MUTANTS OF LEISHMANIA

描述(申请人提供)：锥虫原虫属利什曼原虫的寄生虫是一系列热带疾病的罪魁祸首，全世界有1000多万人受到影响；根据感染者的种类和免疫状况，这种疾病可能是严重的或致命的。在巴西、非洲和地中海盆地，利什曼病是艾滋病患者常见的机会性感染，目前驻扎在中东的许多美军士兵都已被感染，有一种令人担忧的感觉，即利什曼病物种可能正在美国出现或扩大。利什曼原虫的表面覆盖着一种复杂的碳水化合物糖萼，其结构和活性是为满足寄生虫的需要而量身定做的，当寄生虫作为鞭毛状前鞭毛体生长在沙蝇载体中时，或者作为圆形无鞭毛体生长在脊椎动物巨噬细胞吞噬体内时，它在恶劣的环境中愉快地生存并逃避免疫防御。我们的团队和合作者开创了产生突变体的有效方法，并在表面涂层的合成方面存在缺陷，最初专注于丰富的脂磷多糖(LPG)以及结构相关的碳水化合物，如蛋白磷酸多糖(PPG)，最近又专注于通过一种新的线粒体岩藻糖基转移酶作用合成的分子。这些突变体定义了糖共轭合成和毒力所需的重要生物合成蛋白，研究它们对感染周期特定方面的影响有助于更深入地了解它们独特的与重叠的作用。已确定的几种酶显示出相当大的希望作为化疗的靶标，或在开发专注于寄生虫疫苗接种和阻断传播的策略方面具有相当大的前景。

DESCRIPTION (provided by applicant): Parasites of the trypanosomatid protozoan genus Leishmania are responsible for a spectrum of tropical diseases, afflicting more than 10 million people worldwide; depending on the species and immune status of the infected person, this disease can be severe or fatal. In Brasil, Africa and the Mediterranean basin, leishmaniasis is a common opportunistic infection in AIDS patients, many US soldiers now stationed in the Middle East have been infected, and there is a worrisome sense that Leishmania species may be emerging or expanding in the US. The surface of the Leishmania parasite is covered by a complex carbohydrate glycocalyx, whose structure and activities are tailored to meet the parasite's needs when growing in the sand fly vector as flagellated promastigotes, or within vertebrate macrophage phagolysosome as the roundish amastigote, where it survives happily in a hostile environment and evades immune defenses. Our group and collaborators pioneered powerful methods for the generation of mutants defect in the synthesis of the surface coat, originally focusing on the abundant lipophosphoglycan (LPG) as well as structurally related carbohydrates such as proteophosphoglycan (PPG), and more recently on molecules synthesized by the action of a novel mitochondrial fucosyltransefase. These mutants define vital biosynthetic proteins required for glycoconjugate synthesis and virulence, and the study of their impact on specific aspects of the infectious cycle enables a deeper understanding of their unique vs. overlapping roles. Several of the enzymes identified show considerable promise as targets for chemotherapy, or in the development of strategies focusing on parasite vaccination and interruption of transmission.