Mapping Protein Interactions between Filaria and its Wolbachia Endosymbiont

描述(由申请人提供)：丝虫寄生虫困扰着全世界数亿人，并在世界上许多最贫穷的国家代表着严重的公共卫生问题。目前用于抗击这些感染的药物有几个缺点，包括需要非常长的化疗疗程，以及可能产生耐药性。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。大多数人类丝虫病寄生虫物种都含有一种沃尔巴克氏菌属的内共生细菌。这些内生细菌是必不可少的，因为清除内生共生菌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菌的抗生素方案持续时间很长，需要使用一种使用非常有限的药物。因此，有必要开发新的化疗方法，实际上可以利用人类丝虫寄生虫对沃尔巴克氏菌内共生菌丧失的脆弱性。以前的生化和遗传学研究已经证实，宿主和沃尔巴克氏菌之间的沟通对于沃尔巴克氏菌维持自身和在宿主种群中传播是必不可少的。这项提议的总体目标将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.绘制内共生菌与其宿主之间的相互作用组。2.鉴定参与内共生相互作用的马来不动杆菌核编码基因。3.建立参与内共生关系的寄生虫基因的遗传调控和功能网络。由丝虫寄生虫引起的疾病困扰着全世界数亿人，在世界上许多最贫穷的国家都是重大的公共卫生和社会经济问题。由于丝虫病对公共卫生的重要性，三十多年来，国际社会一直支持各种丝虫病控制方案。这些项目的累计支出现在已达数亿美元。然而，由于缺乏有效的工具来抗击这些感染，在消除人类丝虫病方面的进展受到了阻碍。真正缺乏的一个工具是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，控制程序必须保持对寄生虫种群的高度压力，以确保成年雌性寄生虫的有效寿命，这一期限可以延长到12年或更长时间。最近的研究表明，这些寄生虫中的一种胞内细菌对寄生虫的繁殖是必不可少的，从寄生虫中清除这种细菌会导致雌虫不育。如果该计划成功，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，并为人类提供一个有效的新工具来对抗这些寄生虫。

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.