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The role of MIF in hookworm infection and disease

MIF 在钩虫感染和疾病中的作用

基本信息

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
项目类别：
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

项目摘要

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