Molecular negotiations at the host-parasite interface

宿主-寄生虫界面的分子谈判

• 批准号: 326946-2011
• 负责人: Geary, Timothy
• 金额: $ 4.08万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=571875
• 关键词: Molecular; negotiations; host; parasite; interface

Parasitism is the commonest life-style for animals, yet hosts resist almost all parasite species; each host has a set of relatively specific parasites. Host defense systems provide inhospitable conditions for the vast majority of parasite species. The molecular negotiations between parasite and host that enable parasite success underlie a fundamental aspect of life: how to prevent parasitism to conserve nutritional resources (on the part of the host) and how to evade host defenses to reproduce (on the part of the parasite). The molecules deployed in this negotiation are poorly understood; our research aims to develop a better understanding of how parasites overcome host defenses and usurp host resources. We used genomic/proteomic approaches to identify proteins secreted by a filarial parasitic nematode, Brugia malayi, and showed that the main drug for filariasis, ivermectin, blocks protein secretion by the parasite. We will continue work on the molecular basis of the host-parasite interface using several methods. These include intensive studies on how parasite secreted proteins affect host immune responses at the cellular level, based on a deeper understanding of the secretomes of nematodes. We will also investigate interactions between parasites and their hosts based on the release of metabolites which modulate immune responses. Finally, we will resolve how ivermectin persistently sterilizes adult parasites (it does not kill them). Our hypothesis is that the drug inhibits the ingestion of iron bound to host proteins by paralyzing the pharynx. Most nutrients needed by filarial nematodes are obtained via absorption, but iron is tightly bound to host proteins and requires ingestion. Production of microfilariae requires a constant supply of heme, and the irreversible nature of the ivermectin-receptor interaction means that recovery from drug exposure depends on renewal of parasite receptors in target tissues. As host- parasite interactions represent prime drivers of evolution, understanding the interface on a molecular level has deep implications for basic animal biology.

寄生是动物最常见的生活方式，但宿主几乎抵抗所有的寄生虫物种;每个宿主都有一套相对特定的寄生虫。宿主防御系统为绝大多数寄生虫提供了不适宜生存的条件。寄生虫和宿主之间的分子谈判，使寄生虫成功的基础上的一个基本方面的生活：如何防止寄生保存营养资源（对主机的一部分）和如何逃避主机的防御繁殖（对寄生虫的一部分）。在这种谈判中部署的分子知之甚少;我们的研究旨在更好地了解寄生虫如何克服宿主防御和篡夺宿主资源。我们使用基因组/蛋白质组学的方法来确定由丝虫寄生线虫，马来丝虫分泌的蛋白质，并表明，丝虫病的主要药物，伊维菌素，阻断寄生虫的蛋白质分泌。 我们将使用几种方法继续研究宿主-寄生虫界面的分子基础。其中包括深入研究寄生虫分泌的蛋白质如何影响宿主的免疫反应在细胞水平上，基于对线虫的分泌的更深入的了解。我们还将研究寄生虫和它们的宿主之间的相互作用，基于调节免疫反应的代谢物的释放。最后，我们将解决伊维菌素如何持续对成虫寄生虫进行灭菌（它不会杀死它们）的问题。我们的假设是，这种药物通过麻痹咽部来抑制与宿主蛋白质结合的铁的摄入。丝虫线虫所需的大多数营养素都是通过吸收获得的，但铁与宿主蛋白质紧密结合，需要摄入。微丝蚴的产生需要持续供应血红素，伊维菌素-受体相互作用的不可逆性意味着药物暴露的恢复取决于靶组织中寄生虫受体的更新。 由于宿主-寄生虫相互作用代表了进化的主要驱动力，因此在分子水平上理解界面对基础动物生物学具有深刻的意义。