Bacillus Anthracis and Complement

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。然而，一些微生物病原体已经进化为与补体级联的特定组分相互作用并操纵补体级联的特定组分，从而使平衡对宿主不利并有利于病原体。病原体和补体级联反应组分之间的这种动态相互作用为有效的预防和治疗策略提出了挑战和机遇。尽管很重要，但补体系统和炭疽杆菌之间发生的特异性相互作用的知识实际上是不存在的。同样，这种相互作用的生物学后果仍然未知。最近的发现，主要来自我们的小组，表明B的孢子。炭疽已经进化出一种复杂的机制来与补体系统相互作用。我们提出了一种新的模型，其中孢子表面蛋白BclA直接与补体成分C1q和补体调节因子H相互作用。与C1q的相互作用以补体激活依赖性和激活非依赖性的方式介导孢子进入不同类型的宿主细胞，而与因子H的相互作用限制了补体激活的程度并促进病原体存活和持久性。如果这个模型是正确的， 了解补体在炭疽感染发展中的作用，并为以下方面提供共同的机制基础：孢子被不同类型的宿主细胞摄取，孢子诱导的最小炎症反应和孢子在肺中的持续存在，所有这些都是B的致病过程中的重要特征。炭疽病此外，由于BclA在实验动物中显示出保护性，因此了解BclA-补体相互作用的生物学功能将对未来的疫苗开发具有重要意义。此外，本文提出的研究预计将对补体-病原体相互作用产生广泛的影响。因此，提出了两个具体目标。在目的1中，我们将确定孢子表面蛋白BclA与C1q和因子H的结合机制，使用一系列重组蛋白以及表达该蛋白的不同片段的孢子。在目标2中，我们将确定孢子与C1q相互作用的生物学功能 和H因子以及重组BclA片段的疫苗潜力。这将涉及使用缺乏特异性补体成分的小鼠模型和与C1q结合或因子H结合同基因的孢子。还将用BclA的不同片段免疫小鼠，以确定它们对急性和持续性感染的保护效力。该项目将与德克萨斯州休斯顿德克萨斯大学健康科学中心（UTHSC）分子医学研究所免疫学和自身免疫疾病研究中心教授兼主任Rick Wetsel博士合作开展。

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.