Genetics Modifiers of Anthrax Lethal Toxin Induced Pathophysiology

炭疽致死毒素诱导病理生理学的遗传学修饰

基本信息

批准号：
7895640
负责人：
Kenneth Alan Bradley
金额：
$ 37.6万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-17 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7895640
关键词：
Accounting Address Animals Anthrax disease Antigens Automobile Driving Bacillus anthracis Bacteria Biological Process Bioterrorism Bone Marrow Candidate Disease Gene Cells Chromosome Mapping Congenic Mice Congenic Strain Consensus Control Locus Cytolysis Defense Mechanisms Development Disease Event Exhibits Exotoxins Extravasation Functional disorder Genes Genetic Genomics Goals In Vitro Infection Injection of therapeutic agent Knowledge Location Maps Mediating Mediator of activation protein Medical Molecular Morbidity - disease rate Mouse Strains Mus Pathology Phenotype Plasmids Play Process Production Proteins Reproduction spores Resistance Risk Role Severities Testing Therapeutic Toxin United States Variant Virulence anthrax lethal factor base edema factor intravital microscopy macrophage mortality novel therapeutics positional cloning receptor binding response tool trait

项目摘要

Virulence of Bacillus anthracis is associated with the secretion of three plasmid-encoded toxin proteins: protective antigen (PA), lethal factor (LF), and edema factor (EF). LF and EF are catalytic moieties that share the receptor-binding subunit, PA. As a result, two binary toxins are formed: lethal toxin (LT) consisting of PA and Injection of purified LT into animals induces many of the pathologies associated with fulminate anthrax infection indicating that this toxin plays a significant role in disease. However, there is a lack of consensus about how LT causes these pathologies. In response to LT injection, a rapidly induced phenotype was identified in a congenic strain of mice that has a chromosomal segment of the CAST/EiJ strain on an otherwise C57BL/6J background. Our evidence indicates that the genetic factor(s) accounting for this early response also plays role in resistance to spore challenge establishing the significance of this phenotype. We propose to study the early phenotype of advance the understanding of early phathophysiolgical mechanisms and to reveal genetic factors that influence the presentation of LT induced disease well as resistance to spores. First, the qualitative trait loci (QTL) controlling early sensitivity will be mapped by complimentary approaches (i.e., positional cloning and expression QTL analysis). Second, the pathophysiological mechanism driving the early phenotype will be determined by studies that include intravital microscopy and pharmacological approaches. In summary, the early responding congenic strain will be a powerful tool for: 1) identifying genetic factors that regulate sensitivity to LT, 2) elucidating the pathophysiological mechanisms associated with early LT-induced events, and 3) revealing defense mechanisms that are employed by the host in response to LT or spore challenge.

炭疽芽孢杆菌的毒力与三种质粒编码的毒素蛋白的分泌有关：保护性抗原（PA），致死因子（LF）和水肿因子（EF）。 LF和EF是共享受体结合亚基的催化部分，宾夕法尼亚州。结果，形成了两种二元毒素：由PA和将纯化的LT注射到动物中会诱导与促进炭疽感染相关的许多病理，表明这种毒素在疾病中起着重要作用。但是，关于LT如何引起这些病理的共识缺乏共识。为了响应LT注射，在小鼠的先天性菌株中鉴定出一种快速诱导的表型，该菌株在其他C57BL/6J背景上具有铸件/EIJ菌株的染色体段。我们的证据表明，考虑到这种早期反应的遗传因素在抗孢子的挑战中也起着作用，从而确立了这种表型的重要性。我们建议研究进步的早期表型，理解早期的人类学生理机制，并揭示影响LT诱发疾病及其对孢子的抗药性的遗传因素。首先，控制早期灵敏度的定性性状基因座（QTL）将通过免费方法（即位置克隆和表达QTL分析）绘制。其次，驱动早期表型的病理生理机制将取决于包括浸润显微镜和药理方法在内的研究。总而言之，早期反应的股菌株将是一个有力的工具：1）确定调节对LT敏感性的遗传因素，2）阐明与早期LT诱导的事件相关的病理生理机制，以及3）揭示宿主对LT或Spore挑战的宿主采用的防御机制。