Host responses to Mycobacterium infection in Zebrafish.

斑马鱼宿主对分枝杆菌感染的反应。

基本信息

批准号：
9053617
负责人：
LALITA RAMAKRISHNAN
金额：
$ 27万
依托单位：
UNIVERSITY OF CAMBRIDGE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9053617
关键词：
Animals Antibiotic Resistance Antibiotics Apoptosis Apoptotic Bacteria Biological Assay CD36 gene Caspase Cause of Death Cell Culture Techniques Cell Death Cells Cessation of life Chemotaxis Cleaved cell Communicable Diseases Complex Coupled Critical Pathways Development Disease Drug Targeting Drug resistance Epidemic Epithelial Cells Epithelium Funding Gelatinase B Gene Expression Genes Genetic Genetic Polymorphism Genetic Screening Genetic Techniques Genotype Genus Mycobacterium Goals Granuloma Growth HIV Human Image Immune response Immune system Infection Inflammation Intercept Intervention Kinetics Larva Lead Lesion Life Maintenance Mammals Maps Mediating Microscopy Modeling Molecular Molecular Genetics Monitor Mutation Mycobacterium Infections Mycobacterium marinum Mycobacterium tuberculosis Necrosis Optics Outcome Pathway interactions Peptides Phagocytosis Predisposition Process Quantitative Microscopy Recording of previous events Recruitment Activity Relative (related person)Research Resistance Resolution Severities Site Staging Structure Techniques Testing Therapeutic Time Tissues Treatment Protocols Tuberculosis Tumor Necrosis Factor-alpha Vaccines Vertebrates Virulence Virulence Factors Virulent Work Zebrafish base cell type chemokine extracellular genetic variant genome sequencing in vivo leukotriene A4 hydrolase macrophage migration mutant mycobacterial non-compliance pathogen personalized medicine programs rapid technique receptor resistant strain response scavenger receptor tool tuberculosis granuloma

项目摘要

DESCRIPTION (provided by applicant): Tuberculosis (TB), which in humans is caused by Mycobacterium tuberculosis, is one of the leading causes of death from infectious diseases worldwide. There are more TB cases now than at any other time in history and this is largely attributed to the HIV epidemic. Factors that make it difficult to thwart the TB epidemic include the lack of an effective vaccine and the requirement for long multidrug treatment regimens to obtain cures. The latter has led to the selection and spread of extensively drug resistance strains that make TB the lethal disease it was in the pre-antibiotic era. TB results from complex interactions between mycobacteria and their vertebrate hosts. Upon infection by pathogenic mycobacteria, macrophages are recruited to the infection site where they phagocytose the bacteria. However, instead of eradicating the bacteria, macrophages migrate into deeper tissues serving to disseminate the infection. Additional uninfected macrophages are then recruited, and aggregate into the hallmark pathological structure of TB, the granuloma. Long thought to be a host beneficial structure that walls off the infection, we have found that the granuloma, at least in its early stages, serves as a vehicle for bacterial expansion and dissemination. To understand the process of granuloma development, we study Mycobacterium marinum, a close genetic relative of M. tuberculosis, in its natural host, the zebrafish. Zebrafish are genetically tractabl vertebrates with a similar complex immune system to that of mammals and are transparent in the early weeks of development. These features allow a detailed, serial, live-monitoring of infection in animals that have been genetically manipulated. The long term objective of this proposal is to better understand the host-pathogen interactions that occur during granuloma development, with the goal of identifying targets for potential host-directed therapeutics. In this proposal specifically, we will use a variety of molecular and genetic techniques to probe pathways of cell death and recruitment during granuloma development, and to identify pharmacological agents that intercept this process to the benefit of the host.

描述（由申请人提供）：在人类中是由结核分枝杆菌引起的结核病（TB），是全球传染病的主要死亡原因之一。现在的结核病病例比历史上的任何其他时间都多，这主要归因于艾滋病毒的流行。使结核病流行困难的因素包括缺乏有效的疫苗以及需要长多药治疗方案以获得治疗方法的要求。后者导致了广泛的耐药性菌株的选择和传播，这使得TB成为抗生素前时代的致命疾病。 TB是由分枝杆菌与其脊椎动物宿主之间复杂的相互作用引起的。在通过致病性分枝杆菌感染后，将巨噬细胞募集到吞噬细菌的感染部位。但是，巨噬细胞没有消除细菌，而是迁移到较深的组织中，以传播感染。然后募集其他未感染的巨噬细胞，并汇总到TB颗粒瘤的标志性病理结构中。长期以来，人们认为这是一种隔离感染的宿主有益结构，我们发现肉芽肿至少在其早期阶段是细菌膨胀和传播的载体。为了了解肉芽肿发育的过程，我们研究了野生菌（Marinum），这是结核分枝杆菌的亲密遗传亲戚，其自然宿主斑马鱼。斑马鱼是遗传上的脊椎动物，具有与哺乳动物相似的复杂免疫系统，并且在发育初期是透明的。这些特征允许在遗传操纵的动物中对感染的详细，连续的实时监测。该提案的长期目标是更好地了解肉芽肿发育过程中发生的宿主 - 病原体相互作用，目的是确定潜在宿主指导的治疗剂的靶标。在这个提案具体而言，我们将使用各种分子和遗传技术来探测肉芽肿发育过程中细胞死亡和募集的途径，并鉴定出拦截这一过程的药理学剂，以使宿主受益。