Structural Basis of Novel Hookworm Vaccines

新型钩虫疫苗的结构基础

• 批准号: 6963341
• 负责人: OLUWATOYIN Ajibola ASOJO
• 金额: $ 7.35万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6963341
• 关键词: Nematoda; parasite infection mechanism; parasitism; protein sequence; protein structure; protein structure function

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.

描述（由申请人提供）：人类钩虫感染是一种毁灭性疾病，影响着世界上数百万最贫穷的人。这种疾病是由与宿主共同进化的寄生线虫引起的，因此，这些寄生虫是在恶劣微环境中生存的专家，它们以宿主组织为食并逃避宿主的免疫反应。迫切需要替代疗法，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关键阶段的新型疫苗。盖茨基金会发起的疫苗倡议——人类钩虫疫苗倡议（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2个成员Na-ASP-2和Na-ASP-1。两者都来源于主要的人类钩虫寄生虫美洲钩虫（Na）的感染L3幼虫期。asp是一个线虫蛋白家族，其特征是存在至少一个发病机制相关-1（PR-1）结构域。PR-1结构域的功能以及asp免疫调节活性的分子和结构基础尚不清楚。为了设计更好的基于ASP的疫苗，需要澄清这些问题。因此，提出了一个独立的研究项目，采用基于结构的方法来阐明asp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已被求解到1.56埃（蛋白质数据库代码1U53）。此外，还结晶出了一个2pr -1结构域的ASP (Na-ASP-1)，结晶数据高达2.7埃。