Mapping Protein Interactions between Filaria and its Wolbachia Endosymbiont

描述（由申请人提供）：丝状寄生虫折磨着全世界数亿人，在世界上许多最贫穷的国家构成了重大的公共卫生问题。目前用于对抗这些感染的可用药物有几个缺点，包括需要很长的化疗疗程和产生耐药性的可能性。因此，开发治疗这些感染的新药是丝虫病研究领域的一个重要目标。大多数人类丝状寄生虫物种都含有沃尔巴克氏体属的内共生细菌。这些内细菌是必不可少的，因为消除内共生体会导致成年雌性寄生虫的绝育。然而，用于清除寄生虫内共生体的抗生素治疗方案持续时间很长，并且需要使用一种用途非常有限的药物。因此，需要开发新的化疗方法，以实际利用人类丝虫寄生虫对沃尔巴克氏体内共生体丧失的脆弱性。先前的生物化学和遗传学研究已经确定，沃尔巴克氏体内细菌与宿主之间的交流对于沃尔巴克氏体维持自身并在宿主群体中传播是必不可少的。这项提议的总体目标是确定参与这种内共生关系的蛋白质，然后建立参与这一过程的基因的功能网络。该项目的具体目标是：1。绘制内共生体与其宿主的相互作用图。2. 鉴定马来芽孢杆菌核编码基因参与内共生相互作用。3. 研究参与内共生关系的寄生虫基因的遗传调控和功能网络。丝虫病引起的疾病折磨着全世界数以亿计的人，在世界上许多最贫穷的国家构成了严重的公共卫生和社会经济问题。由于丝虫病感染对公共卫生的重要性，国际社会30多年来一直支持各种丝虫病控制规划。这些项目的累计费用现在总计达数亿美元。然而，由于缺乏对抗这些感染的有效工具，消除人类丝虫病的进展受到阻碍。真正缺乏的一种工具是一种杀死或永久绝育成年雌性寄生虫的方法。如果没有这样的工具，控制程序必须在成年雌性寄生虫的有效寿命（可延长至12年或更长时间）内保持对寄生虫种群的高度压力。最近的研究表明，这些寄生虫的细胞内细菌对寄生虫的繁殖至关重要，从寄生虫中消除这种细菌会导致雌性蠕虫的不育。这个项目如果成功的话，将提出新的药物靶点，可以用来杀死这种细菌，从而使雌性寄生虫绝育，并为人类提供一种有效的新工具来对付这些寄生虫。

DESCRIPTION (provided by applicant): Filarial parasites afflict hundreds of millions of individuals worldwide, and represent significant public health problems in many of the poorest countries in the world. The currently available drugs used to combat these infections have several drawbacks, including the need for very long chemotherapeutic courses and the potential for the development of resistance. As a result, the development of new drugs to treat these infections is an important goal in the field of filariasis research. Most of the human filarial parasite species harbor an endosymbiotic bacterium of the genus Wolbachia. These endo-bacteria are essential, as elimination of the endosymbiont leads to sterilization of the adult female parasite. However, the antibiotic regimens that have been used to rid the parasites of the endosymbiont are of very long duration and require the use of a drug whose use is very limited. Thus, the need exists for the development of new chemotherapeutic approaches that can practically exploit the vulnerability of the human filarial parasites to the loss of the Wolbachia endosymbiont. Previous biochemical and genetic studies have established that communication between the host and Wolbachia endobacterium is essential for the Wolbachia to maintain itself and for it to spread throughout the host population. The overall goal of this proposal will be to identify the proteins that are involved in this endosymbiotic relationship and then to establish the functional networks of the genes involved in the process. The specific aims of the project are: 1. To map the interactome of the endosymbiont and its host. 2. To identify B. malayi nuclear-encoded genes involved in the endosymbiotic interaction. 3. To develop genetic regulatory and functional networks of parasite genes involved in the endosymbiotic relationship. The diseases caused by filarial parasites afflict hundreds of millions of individuals worldwide, and represent significant public health and socio-economic problems in many of the poorest countries in the world. Because of the public health importance of filarial infections, the international community has been supporting various filariasis control programs for over thirty years. The cumulative expenses of these programs now total in the hundreds of millions of dollars. However, progress in the elimination of the human filaria has been hampered by the paucity of efficient tools to combat these infections. The one tool that is really lacking is a method to kill or permanently sterilize the adult female parasites. Without such a tool, the control programs must maintain a high degree of pressure on the parasite population for the effective lifespan of the adult female parasite, a period which can extend to 12 years or more. Recent studies indicated that an intracellular bacterium in these parasites is essential for parasite reproduction and that elimination of this bacterium from the parasite results in sterility of the female worm. This program, if successful will suggest new drug targets that may be used to kill this bacterium, thereby sterilizing the female parasite and giving humanity a potent new tool to use against these parasites.