Regulation of Cell Death by Virulent Strains of Francisella tularensis

土拉弗朗西斯菌强毒株对细胞死亡的调控

基本信息

批准号：
8089805
负责人：
MICHAEL J PARMELY
金额：
$ 22.65万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8089805
关键词：
AIM2 gene Abbreviations Address Animal Model Animals Antigens Apoptosis Apoptotic Attenuated Attenuated Vaccines Bacteria Binding Biotin Bone Marrow Caspase Caspase-1 Cell Culture Techniques Cell Death Cell Death Induction Cell Death Signaling Process Cessation of life Clinical Collection Communicable Diseases DNA Nucleotidylexotransferase Development Disease Experimental Models Francisella Francisella tularensis Genetic Geographic Distribution Host Defense Human Immune Immune response Immunity In Situ In Situ Nick-End Labeling In Vitro Infection Inflammatory Interferon Type I Intervention Knowledge Label Laboratory mice Lactate Dehydrogenase Lethal Dose 50 Link Lipopolysaccharides Literature Mediating Modeling Mus Natural Immunity Nitric Oxide Synthase Nucleotides Pathogenesis Pathogenicity Pathway interactions Phase Play Pneumonia Production Property Proteins Publishing Regulation Relative (related person)Reporting Research Respiratory Tract Infections Role Signal Transduction Site Staging Study models System Testing Time Tissues Tularemia Virulence Virulent adaptive immunity anthrax lethal factor base caspase-3 cytotoxic design genetic manipulation human disease in vivo macrophage mortality nonhuman primate novel pathogen preference prevent prototype receptor response trait

项目摘要

DESCRIPTION (provided by applicant): Tularemia is a serious, often lethal infectious disease caused by the intracellular bacterium Francisella tularensis. A sense of the innate immune responses that protect mammalian hosts from Francisella has recently emerged from the study of subspecies that do not cause human disease. However, many of these concepts have not been tested in experimental infection models involving the type A and B strains that constitute the major Francisella pathogens in healthy humans. The long-term objective of this proposal is to determine whether or not inflammasome activation in infected macrophages plays a role in limiting the intracellular survival and replication of virulent Francisella subspecies. Published preliminary findings suggest this may not be the case in the mouse, although apoptotic cell death does occur once bacterial burdens reach high levels. Specific aims of the current project include defining the mechanism by which type A and B Francisella strains regulate pyroptosome activation and the production of type I interferons. Both are important signals for inflammatory casapse-mediated cell death in infected macrophages. Cell culture and a mouse respiratory infection model will be used to define specific steps in inflammasome activation that are regulated by these pathogens and determine the significance of macrophage survival to the course of infection. A second major aim is to use a large collection of clinical Francisella isolates to determine whether the induction of macrophage death is the basis for recently described differences in virulence properties of the Francisella subspecies and subclades that infect humans. Thus, this research challenges an existing paradigm of innate immunity to Francisella, namely that the early death of tissue macrophages provides an important host defense against the pathogen by eliminating a pathogen replication site. Understanding the differences in virulence mechanisms used by experimental model organisms and human Francisella clinical isolates will provide a better understanding of potential interventions that might prevent or treat infections with this dangerous pathogen. PUBLIC HEALTH RELEVANCE: Francisella tularensis is a dangerous bacterial pathogen that causes fatal pneumonia and disseminated disease. The present research is designed to determine the mechanisms of disease and the basis for the virulence of the bacterium, which should suggest interventions that may limit its pathogenicity.

描述（由申请人提供）：Tularemia是一种严重的，通常是由细胞内细菌引起的，是由Francisella tolularensis引起的。最近，保护哺乳动物宿主免受弗朗西斯氏菌的先天免疫反应的感觉来自对不会引起人类疾病的亚种的研究。但是，这些概念中的许多概念尚未在涉及构成健康人的主要弗朗西斯菌病原体的A型和B型菌株的实验感染模型中进行了测试。该提案的长期目标是确定感染巨噬细胞中的炎性体激活是否在限制细胞内存活和重复毒性方济各菌亚种的复制方面起作用。发表的初步发现表明，尽管细菌负担达到高水平，但在小鼠中可能并非如此，尽管确实发生了凋亡细胞死亡。当前项目的具体目的包括定义A型和B型弗朗西斯菌菌株调节拟南芥激活和I型干扰素的产生的机制。两者都是感染巨噬细胞中炎症性cas症介导的细胞死亡的重要信号。细胞培养和小鼠呼吸感染模型将用于定义炎症体激活中受这些病原体调节的特定步骤，并确定巨噬细胞存活与感染过程的重要性。第二个主要目的是使用大量的临床弗朗西斯菌分离株来确定巨噬细胞死亡的诱导是否是最近描述的Francisella subspecies和Subclades感染人类的毒力性质差异的基础。因此，这项研究挑战了对弗朗西斯拉的先天免疫力的现有范式，即组织巨噬细胞的早期死亡通过消除病原体复制部位为病原体提供了重要的宿主防御。了解实验模型生物和人类弗朗西斯拉临床分离株使用的毒力机制的差异将更好地理解潜在的干预措施，这些干预措施可能会阻止或治疗这种危险的病原体感染。公共卫生相关性：Francisella tularensis是一种危险的细菌病原体，会导致致命的肺炎和传播疾病。本研究旨在确定疾病的机制和细菌毒力的基础，这应表明可能限制其致病性的干预措施。