Mapping Protein Interactions between Filaria and its Wolbachia Endosymbiont

绘制丝虫与其沃尔巴克氏体内共生体之间的蛋白质相互作用

• 批准号: 7370744
• 负责人: THOMAS R UNNASCH
• 金额: $ 40.81万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7370744
• 关键词: Adult; Affinity; Antibiotics; Bacteria; Bacteriophages; Binding; Binding Proteins; Biochemical Genetics; Bioinformatics; Biological; Biological Assay; Brugia malayi; Child; Communication; Communities; Condition; Country; Crude Extracts; Development; Disease; Doxycycline; Drug Delivery Systems; Drug usage; Economics; Elements; Enzyme-Linked Immunosorbent Assay; Exhibits; Female; Female sterility; Filariasis; Gene Expression; Genes; Genetic; Genome; Genomics; Goals; Human; Humanities; Hybrids; Individual; Infection; Insecta; International; Longevity; Maps; Metabolic; Methods; Molecular; Nuclear; Numbers; Pan Genus; Parasites; Pathway interactions; Patient currently pregnant; Pattern; Pharmaceutical Preparations; Physiological; Population; Process; Protein Interaction Mapping; Protein-Protein Interaction Map; Proteins; Proteomics; Public Health; RNA; Recombinants; Regulatory Element; Reproduction; Research; Resistance development; Screening procedure; Signal Pathway; Sterilization for infection control; Surface; System; Testing; Tetracycline; Tetracyclines; Time; Transfection; Treatment Protocols; Week; Wolbachia; Woman; Yeasts; cDNA Library; filaria; genome-wide analysis; killings; male; parasite genome; pressure; programs; protein protein interaction; reproductive; response; tool; yeast two hybrid system

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.

描述（由申请人提供）：丝虫寄生虫困扰着全世界数亿人，在世界上许多最贫穷的国家代表着严重的公共卫生问题。目前用于对抗这些感染的药物有几个缺点，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。大多数人类丝虫寄生虫物种具有Wolbachia属的内共生细菌。这些内生细菌是必不可少的，因为内共生体的消除导致成年雌性寄生虫的绝育。然而，已经用于去除内共生体的寄生虫的抗生素方案持续时间非常长，并且需要使用使用非常有限的药物。因此，需要开发新的化学治疗方法，其可以实际利用人类丝虫寄生虫对Wolbachia内共生体损失的脆弱性。先前的生物化学和遗传学研究已经确定，宿主和沃尔巴克氏体内细菌之间的通信对于沃尔巴克氏体维持自身并使其在整个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，然后建立参与该过程的基因的功能网络。该项目的具体目标是：1。绘制内共生体与宿主的相互作用组。2.去辨认B。马来人核编码基因参与内共生相互作用。3.建立寄生虫内共生关系相关基因的遗传调控和功能网络。由丝虫寄生虫引起的疾病折磨着全世界数亿人，并在世界上许多最贫穷的国家中代表着重大的公共卫生和社会经济问题。由于丝虫感染对公共卫生的重要性，国际社会三十多年来一直支持各种丝虫病控制计划。这些计划的累计费用现在总计数亿美元。然而，由于缺乏防治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，控制程序必须对寄生虫种群保持高度的压力，以确保成年雌性寄生虫的有效寿命，这一时期可以延长到12年或更长。最近的研究表明，这些寄生虫中的细胞内细菌是寄生虫繁殖所必需的，从寄生虫中消除这种细菌会导致雌性蠕虫不育。如果成功，该计划将提出新的药物靶点，可用于杀死这种细菌，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抗这些寄生虫。