In vivo panning for schistosome protective epitopes

体内淘选血吸虫保护性表位

基本信息

批准号：
6919822
负责人：
Charles Bix Shoemaker
金额：
$ 19.81万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-15 至 2008-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by the applicant): Schistosomiasis afflicts several hundred million people, causing substantial morbidity and premature death as well as major economic hardship in many developing countries. Over a billion people are at risk of infection. Advances in genomics and proteomics, as well as new technologies such as phage display and recombinant antibodies, offer important new opportunities to develop and test hypotheses relating to these worm parasites and for new schistosomiasis control strategies. Schistosomes are trematode worms that are able to survive for many years within the vasculature of permissive vertebrate hosts. Although schistosomes reportedly possess a variety of immune evasive tools, these blood flukes clearly can become susceptible to immune killing by effectors mediated by antibody directed against the host-exposed tegument. Compelling evidence comes from the rat model, which, unlike mice and humans, becomes strongly immune to schistosomiasis mansoni, and produces antibodies against adult worm surface epitopes that direct the killing of larval and adult schistosomes. Based on these and other data, we hypothesize that schistosomes can be killed in vivo through an immune process that is mediated by protective antibodies directed against a discrete subset of worm surface epitopes. In this R21 grant application, we propose to employ an innovative in vivo phage display technique to identify single-chain antibodies (scFvs) able to bind to the surface of schistosomes as they reside within their host and then test these antibodies for their ability to direct killing of the parasites. The Specific Aims are: #1. Use "in vivo panning" of an antibody (scFv) phage display library prepared from rats immune to schistosomiasis to identify and then characterize host-interactive surface epitopes. #2. Engineer recombinant antibodies that bind to host-interactive schistosome epitopes and test their ability to mediate parasite killing within mice. This research is designed to identify new targets of protective immunity that will serve as vaccine candidates. Furthermore, it will produce new information on the biochemistry of the host-interactive parasite surface in vivo and create genetically modifiable scFv reagents that will lead to a range of unique research opportunities to investigate helminth parasite rejection and immune evasion strategies.

描述（由申请人提供）：血吸虫病困扰着数亿人，在许多发展中国家造成大量发病和过早死亡以及重大经济困难。超过十亿人面临感染风险。基因组学和蛋白质组学的进步，以及噬菌体展示和重组抗体等新技术，为开发和测试与这些蠕虫寄生虫相关的假设以及新的血吸虫病控制策略提供了重要的新机会。血吸虫是一种吸虫蠕虫，能够在允许的脊椎动物宿主的脉管系统中存活多年。尽管据报道血吸虫拥有多种免疫逃避工具，但这些血吸虫显然容易受到针对宿主暴露外皮的抗体介导的效应器的免疫杀伤。令人信服的证据来自大鼠模型，与小鼠和人类不同，大鼠模型对曼氏血吸虫病具有很强的免疫力，并产生针对成虫表面表位的抗体，直接杀死幼虫和成虫血吸虫。基于这些和其他数据，我们假设血吸虫可以通过免疫过程在体内被杀死，该免疫过程是由针对蠕虫表面表位的离散子集的保护性抗体介导的。在此 R21 拨款申请中，我们建议采用创新的体内噬菌体展示技术来识别单链抗体 (scFv)，当它们驻留在宿主体内时能够与血吸虫表面结合，然后测试这些抗体的直接定向能力杀死寄生虫。具体目标是：#1。使用从对血吸虫病免疫的大鼠中制备的抗体 (scFv) 噬菌体展示文库进行“体内淘选”，以识别并表征宿主相互作用的表面表位。 #2.设计重组抗体，使其与宿主相互作用的血吸虫表位结合，并测试它们介导小鼠体内寄生虫杀灭的能力。这项研究旨在确定可作为候选疫苗的保护性免疫的新目标。此外，它将产生关于体内宿主相互作用的寄生虫表面生物化学的新信息，并创建可基因修饰的 scFv 试剂，这将为研究蠕虫寄生虫排斥和免疫逃避策略带来一系列独特的研究机会。