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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 PA 的催化部分。结果形成两种二元毒素：致命毒素（LT），由 PA 和将纯化的 LT 注射到动物体内会诱发许多与暴发性炭疽感染相关的病理，表明这种毒素在疾病中发挥着重要作用。然而，对于 LT 如何导致这些病变缺乏共识。为了响应 LT 注射，在同系小鼠品系中鉴定出快速诱导的表型，该小鼠品系在 C57BL/6J 背景上具有 CAST/EiJ 品系的染色体片段。我们的证据表明，导致这种早期反应的遗传因素也在对孢子挑战的抵抗中发挥作用，从而确立了这种表型的重要性。我们建议研究早期表型，以促进对早期病理生理机制的理解，并揭示影响 LT 诱导疾病表现以及对孢子抗性的遗传因素。首先，控制早期敏感性的质量性状基因座 (QTL) 将通过互补方法（即位置克隆和表达 QTL 分析）进行定位。其次，驱动早期表型的病理生理机制将通过包括活体显微镜和药理学方法在内的研究来确定。总之，早期响应的同源菌株将成为一个强大的工具：1）识别调节对 LT 敏感性的遗传因素，2）阐明与早期 LT 诱导事件相关的病理生理机制，3）揭示宿主响应 LT 或孢子挑战所采用的防御机制。