Immune modualtion of schistosome development

描述（由申请人提供）：全球至少有20亿人患有寄生虫感染，其中大多数居住在发展中国家。蠕虫与病毒、细菌和原生生物的不同之处在于，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。据信，寄生虫的发育决定受到宿主因素的影响，并为寄生虫提供了一种应对宿主内不断变化的条件的手段。本提案的总体目标是利用小鼠血吸虫感染模型，对参与这些相互作用的信号和受体进行分子理解。这一知识将揭示新的机会，以破坏蠕虫的生命周期为治疗和预防的目的。血吸虫属吸虫影响着全世界2亿人，是一种有用的、重要的致病蠕虫实验室模型。涉及mansoni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CD4+ T细胞在向发育中的蠕虫传递信号中起着核心作用。此外，CD4+ T细胞和发育中的血吸虫之间发生密切的物理相互作用。本研究的具体目的是确定调节血吸虫发育的宿主分子。由肝CD4+ T细胞产生的候选分子将使用阵列技术和支持分子技术系统地鉴定。然后，将使用转基因小鼠和正在发育的寄生虫培养系统在体内测试合适的候选物的调节活性。特异性目标2提出通过信号序列陷阱文库筛选方法来鉴定参与CD4+ T细胞物理相互作用的血吸虫分子。具体目的3是确定野生型小鼠正常寄生虫和免疫缺陷动物减毒寄生虫之间明显表型差异背后的基因转录分子差异。这一特定目标将利用新兴的阵列技术和支持分子技术来鉴定在寄生虫的两种表型状态下差异表达的基因。鉴定出的基因将为后续研究提供有价值的寄生虫发育分子标记。

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.