The role of MIF in hookworm infection and disease

MIF 在钩虫感染和疾病中的作用

• 批准号: 7463266
• 负责人: MICHAEL CAPPELLO
• 金额: $ 3.03万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-15 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7463266
• 关键词: Active Immunization; Adult; Ancylostoma (genus); Anemia; Animal Model; Antibodies; Area; Binding; Biochemistry; Biological; Biological Assay; Blood capillaries; Cellular biology; Clinical; Complementary DNA; Data; Developed Countries; Developing Countries; Disease; Drug resistance; Environment; Enzyme-Linked Immunosorbent Assay; Epitopes; Evolution; Future; Gene Expression; Gene Silencing; Growth; Hamsters; Health; Helminths; Hemorrhage; Homologous Gene; Hookworm Infections; Hookworms; Human; Human Cloning; Immune response; Immunization; Immunoglobulin G; Immunohistochemistry; Immunology; In Vitro; Infection; Infection prevention; Inflammatory; Inflammatory Response; Interdisciplinary Study; Intervention; Intestinal Mucosa; Intestines; Kinetics; Knowledge; Life; Ligand Binding; Light; MIF gene; Malnutrition; Measurement; Mediating; Migration Inhibitory Factor; Modeling; Molecular; Molecular Mechanisms of Action; Monitor; Mus; Nematoda; Parasites; Pathogenesis; Predisposition; Production; Protein Binding; Proteins; RNA Interference; Recombinants; Research Personnel; Role; Sanitation; Signal Transduction; Site; Source; Specificity; Staging; Surface; Techniques; Testing; Tissue-Specific Gene Expression; Tissues; Universities; Vaccinated; Vaccines; Virulence Factors; Work; X-Ray Crystallography; base; capillary; cytokine; design; factor A; feeding; gastrointestinal; improved; in vivo; inhibitor/antagonist; innovation; macrophage; migration; novel; novel strategies; phenylpyruvate tautomerase; receptor; response; secretory protein; three dimensional structure; vaccine development

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.

钩虫感染是发展中国家营养不良和贫血的主要原因。超过十亿 人们感染了这些吸血线虫寄生虫，它们附着在肠粘膜上并进食 来自撕裂的毛细血管。尽管存在宿主，钩虫仍可在肠道内存活数年 炎症反应。迄今为止，人们对成虫钩虫阻断的机制知之甚少。 为了生存而产生的先天性和后天性宿主免疫反应的组成部分。一个 eDNA 对应于 哺乳动物细胞因子巨噬细胞迁移抑制因子（MIF）的同源物最近已被克隆 来自人类钩虫 锡兰钩虫 (Ancylostoma ceylanicum)。初步数据表明重组A. ceylanicum MIF (rAceMIF) 具有酶活性，可与人类蛋白质竞争结合最近鉴定的 MIF受体CD74。我们假设钩虫 MIF 同源物有效调节宿主免疫 反应以促进寄生虫在粘膜表面的存活。该项目的目的是表征 MIF 在钩虫感染和疾病发病机制中的作用。 AceMIF 的作用机制是 使用 MIF 功能的体外研究进行表征，包括互变异构酶活性、巨噬细胞迁移和 促炎细胞信号传导。 rAceMIF 与 CD74 结合的动力学将被表征，其三个 尺寸结构将使用X射线晶体学来阐明。 AceMIF 基因表达将 体内特征，以记录其阶段特异性，以及 AceMIF 生产的来源 成虫钩虫将通过免疫组织化学进行表征。平行研究将分析组织特异性 使用完全允许的钩虫动物模型，宿主 MIF 的表达响应钩虫感染。 锡兰尼库姆。 AceMIF 在钩虫贫血和生长迟缓发病机制中的作用也将被研究 使用疫苗和靶向基因沉默方法进行表征。对免疫接种的反应将是 通过 ELISA 监测，以及针对 AceMIF 的抗体预防钩虫贫血的程度 将使用临床参数和蠕虫负荷测量来评估生长延迟。这些研究将 表征了多功能人类细胞因子的这种新型蠕虫同源物，最终确定了其作用 MIF 在钩虫病发病机制中的作用。