Molecular negotiations at the host-parasite interface

寄生是动物最常见的生活方式，但宿主几乎抵抗所有寄生虫物种；每个宿主都有一组相对特定的寄生虫。宿主防御系统为绝大多数寄生虫物种提供了不适宜居住的条件。寄生虫和宿主之间的分子谈判使寄生虫得以成功，这是生命的一个基本方面：如何防止寄生以保存营养资源(在宿主方面)，以及如何逃避宿主防御以繁殖(在寄生虫方面)。在这场谈判中部署的分子知之甚少；我们的研究旨在更好地理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/蛋白质组的方法来鉴定丝虫寄生线虫--马来丝虫所分泌的蛋白质，结果表明，治疗丝虫病的主要药物伊维菌素能阻断这种寄生虫的蛋白质分泌。 我们将继续使用几种方法对宿主-寄生虫界面的分子基础进行研究。这些研究包括在深入了解线虫分泌体的基础上，深入研究寄生虫分泌的蛋白质如何在细胞水平上影响宿主免疫反应。我们还将根据调节免疫反应的代谢物的释放来研究寄生虫与其宿主之间的相互作用。最后，我们将解决伊维菌素如何持久地杀灭成虫(它不会杀死它们)。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取。丝虫所需的大部分营养物质是通过吸收获得的，但铁与宿主蛋白质紧密结合，需要摄取。微丝虫的产生需要持续的血红素供应，而伊维菌素-受体相互作用的不可逆性意味着从药物暴露中恢复依赖于靶组织中寄生虫受体的更新。 由于宿主-寄生虫的相互作用代表着进化的主要驱动力，在分子水平上理解这种界面对于基础动物生物学具有深远的意义。

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.