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与补体级联的特定成分相互作用并操纵，打破了对宿主不利而对病原体有利的平衡。这种病原体和补体级联成分之间的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。尽管其重要性，补体系统和炭疽杆菌之间发生的具体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，表明炭疽芽孢杆菌已经进化出一种复杂的机制来与补体系统相互作用。我们提出了一个新的模型，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相互作用介导孢子以补体激活依赖和激活不依赖的方式进入不同类型的宿主细胞，而与因子H相互作用限制补体激活的程度，促进病原体的生存和持续。如果这个模型是正确的，它将在

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.