Structural Basis of Novel Hookworm Vaccines

描述(申请人提供)：人类钩虫感染是一种毁灭性的疾病，影响着世界上数百万最贫穷的人。这种疾病是由寄生线虫引起的，这些线虫与宿主共同进化，因此，这些寄生虫是在恶劣的微环境中生存的专家，在那里它们以宿主组织为食，逃避宿主的免疫反应。迫切需要替代疗法，以改善感染者的健康状况，防止新患者感染，以减轻这些疾病的经济和社会负担。一种可行的方法是开发针对线虫寄生虫复杂生命周期中关键阶段的新型疫苗。盖茨基金会赞助的疫苗倡议--人体钩虫疫苗倡议(HHVI)--已经确定了候选疫苗。HHVI候选疫苗包括钩虫分泌蛋白(ASP)家族的两个成员Na-ASP-2和Na-ASP-1。两者都来自感染美洲钩虫(Necatur americanus，Na)的L3幼虫阶段，Necatur americanus(Na)是人类主要钩虫寄生虫。天冬氨酸转运蛋白是一个线虫蛋白家族，其特征是至少存在一个致病相关1(PR-1)结构域。PR-1结构域的功能尚不清楚，其免疫调节活性的分子和结构基础也不清楚。这些都需要澄清，以便设计出更好的基于ASP的疫苗。因此，提出了一个自成一体的研究项目，采用基于结构的方法来阐明天冬氨酸的功能和作用机制。作为这些研究的一部分，ASP的第一个结构，单个PR-1结构域Na-ASP-2已被解算为1.56埃(蛋白质数据库代码1U53)。此外，还合成了一个2-PR-1结构域的天冬氨酸(Na-ASP-1)，晶化数据达2.7埃。

DESCRIPTION (provided by applicant): Human hookworm infection is a devastating disease which affects millions of the world's poorest people. This disease is caused by parasitic nematodes, that co-evolved with their hosts, consequently, these parasites are experts at surviving in hostile microenvironments where they feed on host tissues and evade host immune responses. There is a desperate need for alternative therapies that ameliorate the health status of infected people, prevent the infection of new patients, in order to alleviate the economic, and social burdens of these diseases. A viable approach is to develop novel vaccines that target critical stages in the complex life-cycles of the nematode parasite. A Gates-foundation sponsored vaccine initiative, the Human Hookworm Vaccine Initiative (HHVI) has identified vaccine candidates. HHVI vaccine candidates include Na-ASP-2 and Na-ASP-1, 2 members of the Ancylostoma secreted protein (ASP) family. Both are derived from infective L3 larval stage of Necatur americanus (Na), the predominant human hookworm parasite. The ASPs are a family of nematode proteins that are characterized by the presence of at least 1 pathogenesis related-1(PR-1) domain. The functions of the PR-1 domain are unclear as are molecular and structural basis for immune modulating activity of the ASPs. These need to be clarified in order to design better ASP based vaccines. Thus, a self-contained research project that takes a structure based approach to elucidate the function and mechanisms of action the ASPs is proposed. As part of these studies, the first structure of an ASP, the single PR-1 domain Na-ASP-2 has been solved to 1.56 Angstroms (protein data bank code 1U53). In addition, a 2 PR-1 domain ASP (Na-ASP-1) has been crystallized with data up to 2.7 Angstroms.