Bacillus Anthracis and Complement

炭疽杆菌和补体

• 批准号: 8522147
• 负责人: YI XU
• 金额: $ 33.98万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-03 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8522147
• 关键词: Acute; Affect; Amino Acids; Animals; Anthrax disease; Autoimmune Diseases; Bacillus anthracis; Bacillus anthracis spore; Bacterial Adhesins; Binding; Binding Sites; Biological; Biological Process; Blood; Cells; Chimeric Proteins; Collaborations; Collagen; Complement; Complement 1q; Complement Activation; Complement Factor H; Development; Digestion; Enterococcus; Equilibrium; Event; Future; Genus staphylococcus; HIV; Health Sciences; Host Defense; Immune system; Immunization; Immunology; Infection; Inflammatory Response; Institutes; Kinetics; Knowledge; Lead; Length; Liquid substance; Lung; Maps; Mediating; Membrane Proteins; Modeling; Molecular; Molecular Medicine; Mus; Mutation; Pathology; Personal Communication; Preventive; Process; Proteins; Recombinant Proteins; Recombinants; Recruitment Activity; Reporting; Reproduction spores; Research; Role; Series; Surface; Testing; Texas; Therapeutic; Tissue Survival; Universities; Vaccines; base; combat; complement system; in vivo; insight; microbial; microorganism; mouse model; novel; pathogen; professor; protective efficacy; uptake; vaccine development

DESCRIPTION (provided by applicant): The complement system is a key component of a host's defense against microorganisms. However, some microbial pathogens have evolved to interact with and manipulate specific components of the complement cascade, tipping the balance against the host and in favor of the pathogen. This dynamic interplay between pathogens and components of the complement cascade presents challenges and opportunities for effective preventive and therapeutic strategies. Despite the importance, knowledge of the specific interactions that occur between the complement system and Bacillus anthracis is virtualy non-existent. Likewise, the biological consequences of such interactions remain unknown. Recent discoveries, primarily from our group, suggest that spores of B. anthracis have evolved a sophisticated mechanism to interact with the complement system. We propose a novel model in which the spore surface protein BclA directly interacts with complement component C1q and complement regulator factor H. Interaction with C1q mediates spore entry into different types of host cells in both a complement activation-dependent and activation-independent manner while interaction with factor H limits the extent of complement activation and promotes pathogen survival and persistence. If this model is correct, it will be significant in understanding the role of complement in the development of anthrax infections as well as providing a common mechanistic basis for; spore uptake by different types of host cells, the minimal inflammatory responses induced by spores and spore persistence in the lung, all of which are important features in the pathogenic process of B. anthracis. In addition, as BclA was shown to be protective in experimental animals, understanding the biological functions of BclA-complement interactions will have significant implications to future vaccine development. Furthermore, the studies proposed here are expected to have broad implications to complement-pathogen interactions in general. Consequently, two specific aims are proposed. In aim 1, we will determine the binding mechanisms of spore surface protein BclA to C1q and factor H, using a series of recombinant proteins as well as spores expressing different segments of the protein. In aim 2, we will determine the biological functions of spore interactions with C1q and factor H and the vaccine potential of recombinant BclA fragments. This will involve using mouse models deficient in specific complement components and spores isogenic for C1q binding or factor H binding. Mice will also be immunized with different fragments of BclA to determine their protective efficacy against both acute and persistent infections. The project will be carried out in collaboration with Dr. Rick Wetsel, Professor and Director, Research Center for Immunology and Autoimmune Diseases, Institute of Molecular Medicine, University of Texas Health Science Center (UTHSC), Houston, Texas.

描述（由申请人提供）：补体系统是宿主防御微生物的关键组成部分。但是，一些微生物病原体已经演变成与补体级联反应的相互作用并操纵特定组成部分，将平衡与宿主的平衡相提并论，并有利于病原体。病原体与补充级联的组成部分之间的这种动态相互作用提出了有效的预防和治疗策略的挑战和机会。尽管很重要，但对补体系统和炭疽芽孢杆菌之间发生的特定相互作用的了解实际上是不存在的。同样，这种相互作用的生物学后果仍然未知。最近的发现主要来自我们小组，这表明炭疽芽孢杆菌的孢子已经发展出与补体系统相互作用的复杂机制。我们提出了一个新型模型，其中孢子表面蛋白BCLA直接与补体组件C1Q和补体调节因子H相互作用。与C1Q的相互作用可在依赖于激活的激活依赖性和与激活的方式中介导孢子进入不同类型的宿主细胞，同时与HI的相互作用限制了互补的活化激活和促进​​patedentation and pantenogent and Pereses fatenogen and Peressence and Persessence and Peressence and servisensence and Peressentence and Peressencence and servisensence and servisensence and servenence。如果此模型正确，它将很重要 了解补体在炭疽感染的发展中的作用，并提供共同的机械基础；不同类型的宿主细胞的孢子吸收，肺中孢子和孢子持续性引起的最小炎症反应，所有这些都在炭疽芽孢杆菌致病过程中都是重要的特征。此外，由于BCLA在实验动物中被证明具有保护性，因此了解BCLA汇编相互作用的生物学功能将对未来的疫苗开发产生重大影响。此外，这里提出的研究预计将对一般的补体 - 病原体相互作用具有广泛的影响。因此，提出了两个具体目标。在AIM 1中，我们将使用一系列重组蛋白以及表达蛋白质不同片段的孢子来确定孢子表面蛋白BCLA与C1Q和因子H的结合机制。在AIM 2中，我们将确定与C1Q相互作用的生物学功能 H和因子H以及重组BCLA片段的疫苗潜力。这将涉及使用缺乏特定补体成分和孢子的小鼠模型用于C1Q结合或因子H结合。小鼠还将用BCLA的不同片段对小鼠进行免疫，以确定它们针对急性和持续感染的保护效果。该项目将与德克萨斯州休斯敦大学健康科学中心（UTHSC）的分子医学研究所（UTHSC）的分子医学研究所教授兼总监Rick Wetsel博士合作进行。