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到能够与补体级联的特定成分相互作用并操纵补体级联的特定成分，从而打破对宿主不利的平衡并有利于病原体。病原体和补体级联成分之间的这种动态相互作用为有效的预防和治疗策略带来了挑战和机遇。尽管很重要，但对补体系统和炭疽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。主要来自我们小组的最新发现表明，炭疽芽孢杆菌的孢子已经进化出一种与补体系统相互作用的复杂机制。我们提出了一种新模型，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 的相互作用介导孢子以补体激活依赖和激活独立的方式进入不同类型的宿主细胞，而与因子 H 的相互作用限制补体激活的程度并促进病原体的存活和持久性。如果这个模型正确的话，将会有重大意义 了解补体在炭疽感染发展中的作用并提供共同的机制基础；不同类型宿主细胞对孢子的摄取、孢子引起的最小炎症反应以及孢子在肺中的持久性，所有这些都是炭疽杆菌致病过程的重要特征。此外，由于 BclA 在实验动物中被证明具有保护作用，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产生重大影响。此外，这里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。在目标 1 中，我们将使用一系列重组蛋白以及表达该蛋白不同片段的孢子来确定孢子表面蛋白 BclA 与 C1q 和 H 因子的结合机制。在目标 2 中，我们将确定孢子与 C1q 相互作用的生物学功能 以及 H 因子和重组 BclA 片段的疫苗潜力。这将涉及使用缺乏特定补体成分和 C1q 结合或 H 因子结合等基因孢子的小鼠模型。还将用不同的 BclA 片段对小鼠进行免疫，以确定它们对急性和持续性感染的保护功效。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。 公共卫生相关性：补体系统是宿主防御微生物的重要组成部分。该项目旨在研究炭疽杆菌（炭疽病的病原体）的孢子如何主动参与补体系统的组成部分以及这种参与的生物学后果。该项目可能会为感染建立过程中一些关键事件的分子机制提供新的重要见解，并可能带来更好的疫苗来对抗炭疽感染。

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. PUBLIC HEALTH RELEVANCE: The complement system is an essential component in host defense against microorganisms. The proposed project aims to investigate how spores of Bacillus anthracis, the causative agent for anthrax, actively engage components of the complement system and the biological consequences of such engagement. The project is likely to provide new and important insights into the molecular mechanisms underlying some of the key events in the establishment of infections and may lead to better vaccines to combat anthrax infections.