Immune modualtion of schistosome development

描述(申请人提供)：全球至少有20亿人患有蠕虫感染，其中大部分居住在发展中国家。蠕虫不同于病毒、细菌和原生动物，因为它们表现出复杂的生命周期，通常涉及多种发育途径，导致不同的表型结果。发育决定被认为受到寄主因素的影响，并为寄生虫提供了一种对寄主内不断变化的条件做出反应的手段。这项建议的广泛目标是利用血吸虫感染的小鼠模型，发展对参与这些相互作用的信号和受体的分子理解。这一知识应该揭示出新的机会，为治疗和预防目的扰乱蠕虫的生命周期。影响全球2亿人的血吸虫属吸虫构成了致病蠕虫的有用和重要的实验室模型。涉及曼氏血吸虫的研究表明，哺乳动物宿主内正常发育的启动依赖于寄生虫接收适当的宿主信号。肝脏CD4T细胞在将这种信号传递给发育中的蠕虫的过程中发挥着核心作用。此外，CD4T细胞和发育中的血吸虫之间发生了密切的物理相互作用。这项提议的具体目标1是确定负责调节血吸虫发育的宿主分子。将利用阵列技术和辅助分子技术系统地鉴定肝脏CD4T细胞产生的候选分子。然后，将使用转基因小鼠在体内测试合适的候选者的调节活性，并使用正在开发的寄生虫培养系统在体外测试调节活性。特定目的2建议通过信号序列捕获文库筛选方法来鉴定参与与CD4T细胞的物理相互作用的血吸虫分子。具体目标3是确定导致来自野生型小鼠的正常寄生虫和来自免疫缺陷动物的减毒寄生虫之间明显表型差异的基因转录的分子差异。这一特定目标将利用新兴的阵列技术和辅助分子技术来识别在寄生虫的两种表型状态下差异表达的基因。已识别的基因将为后续研究提供有价值的寄生虫发展的分子标记。

DESCRIPTION (provided by applicant): At least two billion people suffer from helminth infections globally, the majority of whom reside in the developing world. Helminths differ from viruses, bacteria and protists in that they exhibit complex life cycles, often involving multiple developmental pathways that result in different phenotypic outcomes. Developmental decisions are believed to be influenced by host factors and provide the parasite with a means to respond to changing conditions within the host. The broad objectives of this proposal are to develop a molecular understanding of the signals and receptors involved in these interactions, using a murine model of schistosome infection. This knowledge should reveal new opportunities to disrupt helminth life cycles for therapeutic and prophylactic purposes. Trematodes of the genus Schistosoma, which affect 200 million people worldwide, constitute a useful and important laboratory model of pathogenic helminths. Studies involving S. mansoni have demonstrated that initiation of normal development within the mammalian host is dependent on the receipt of appropriate host signals by the parasite. Hepatic CD4+ T cells play a central role in delivering this signals to the developing worm. Further, an intimate physical interaction occurs between CD4+ T cells and developing schistosomes. Specific aim 1 of this proposal it to identify the host molecules responsible for modulating schistosome development. Candidate molecules produced by hepatic CD4+ T cells will be systematically identified using array technology and supporting molecular techniques. Suitable candidates will then be tested for modulatory activity in vivo, using genetically altered mice, and in vitro, using a developing parasite culture system. Specific aim 2 proposes to identify schistosome molecules that participate in the physical interaction with CD4+ T cells by employing a signal sequence trap library screening approach. Specific aim 3 is to identify the molecular differences in gene transcription that underlie the obvious phenotypic differences between normal parasites from wild type mice and attenuated parasites from immunodeficient animals. This specific aim will make use of emerging array technology and supporting molecular techniques to identify genes that are differentially expressed in the two phenotypic states of the parasite. Identified genes will provide valuable molecular markers of parasite development for use in subsequent studies.