The role of MIF in hookworm infection and disease

钩虫感染是发展中国家营养不良和贫血的主要原因。十几亿 人们感染了这些吸血的线虫寄生虫，它们附着在肠道粘膜上并进食 从撕裂的毛细血管。钩虫可能会在肠道内存活数年，尽管存在宿主。 炎症反应。到目前为止，对成虫阻断钩虫的机制知之甚少。 先天和获得性宿主免疫反应的组成部分，以求生存。一个对应于 哺乳动物细胞因子巨噬细胞移动抑制因子(MIF)的同源物最近被克隆 来自人类钩虫钩口线虫。初步数据表明，重组头孢曲霉 MIF(RAceMIF)具有酶活性，并与人类蛋白竞争结合最近鉴定的 MIF受体CD74。我们假设钩虫MIF同源物有效地调节宿主免疫。 反应，以促进寄生虫在粘膜表面的生存。这个项目的目的是描述 MIF在钩虫感染和疾病发病机制中的作用AceMIF的作用机制将是 以体外研究MIF功能为特征，包括互变构酶活性、巨噬细胞迁移和 促炎症细胞信号。RAceMIF与CD74结合的动力学将被表征，它的三个 空间结构将用X射线结晶学来阐明。AceMIF基因表达将是 体内特征，以证明其阶段特异性，以及AceMIF在体内产生的来源 成虫将用免疫组织化学方法鉴定。平行研究将分析特定组织 在钩虫感染的动物模型上，宿主MIF的表达。 仙人掌。AceMIF在钩虫贫血和生长迟缓的发病机制中的作用也将是 使用疫苗和靶向基因沉默方法来表征。对免疫接种的反应将是 通过ELISA监测，以及针对AceMIF的抗体对钩虫性贫血的保护程度 并将使用临床参数和蠕虫负载测量来评估生长延迟。这些研究将 鉴定一种多功能人类细胞因子的新型蠕虫同源物，最终决定其作用 MIF在钩虫病发病机制中的作用。

Hookworm infection is a leading cause of malnutrition and anemia in the developing world. More than one billion people are infected with these bloodfeeding nematode parasites, which attach to the intestinal mucosa and feed from lacerated capillaries. Hookworms may survive for years within the intestine, despite the presence of a host inflammatory response. To date, little is known about the mechanisms by which adult hookworms block components of the innate and acquired host immune responses in order to survive. A eDNA corresponding to a homologue of the mammalian cytokine Macrophage Migration Inhibitory Factor (MIF) has recently been cloned from the human hookworm Ancylostoma ceylanicum. Preliminary data suggest that the recombinant A. ceylanicum MIF (rAceMIF) is enzymatically active and competes with the human protein for binding to the recently identified MIF receptor CD74. We hypothesize that the hookworm MIF homologue effectively modulates the host immune response in order to facilitate parasite survival at the mucosal surface. The aim of this project is to characterize the role of MIF in the pathogenesis of hookworm infection and disease. The mechanism of action of AceMIF will be characterized using in vitro studies of MIF function, including tautomerase activity, macrophage migration, and pro-inflammatory cell signaling. The kinetics ofrAceMIF binding to CD74 will be characterized, and its three dimensional structure will be elucidated using X-ray crystallography. AceMIF gene expression will be characterized in vivo in order to document its stage specificity, and the source of AceMIF production within the adult hookworm will be characterized by immunohistochemistry. Parallel studies will analyze tissue specific expression of host MIF in response to hookworm infection using a fully permissive animal model of A. ceylanicum. The role of AceMIF in the pathogenesis of hookworm anemia and growth delay will also be characterized using both vaccine and targeted gene silencing approaches. The response to immunization will be monitored by ELISA, and the degree to which antibodies directed at AceMIF protect against hookworm anemia and growth delay will be assessed using clinical parameters and worm burden measurements. These studies will characterize this novel helminth homologue of a multi functional human cytokine, ultimately determining the role of MIF in the pathogenesis of hookworm disease.