Structure and Function of the B. Anthracis Exosporium

炭疽杆菌是炭疽病的起因，已被外国政府和恐怖组织发展成为大规模杀伤性武器。最近炭疽杆菌在美国的释放，带来了严重的后果，暴露了对这一威胁做出更有效反应的必要性。炭疽杆菌之所以被用作武器，很大程度上是因为它能形成高抵抗力的孢子，可用于爆炸性武器和恐怖分子装置。孢子通过皮肤磨损和摄入或吸入进入体内，然后萌发并生长为营养细胞。当内部组织发生生长时，寄主通常在几天内死亡。 炭疽杆菌的天然菌株对常见抗生素敏感；然而，大规模使用这些抗生素来预防炭疽病在后勤上是困难的，在医学上也是危险的。此外，未来可能会使用耐药菌株。此外，目前的炭疽疫苗已被证明存在问题。因此，需要新的战略来应对炭疽威胁，这些战略可能需要详细了解哺乳动物免疫系统与炭疽芽胞最外表面--外孢子体之间的相互作用。外孢子菌是与宿主防御的主要相互作用部位，是表面抗原的来源，也是排除抗体和抗体的半渗透屏障。 具有破坏性的酶。外孢子体由准晶基层和外部毛状绒毛组成。 外孢子菌大约50%的质量似乎是蛋白质，大约20种独特的物种，包括糖蛋白。初步研究表明，外孢子菌蛋白在孢子毒力中起作用。 该项目的目标是确定外孢子菌外表面的内容、结构和功能。最重要的是在表面暴露的蛋白质和糖蛋白的毒力中的作用。具体地说，我们将(1)识别这些蛋白质，进行改变它们的突变，并使用小鼠模型检查这些突变对宿主细胞相互作用和毒力的影响。(2)我们将定位关键外孢子蛋白的表位，如毛状NAP的胶原样蛋白(BCLA)，并检测抗体与这些表位结合的效果。特别令人感兴趣的是结合外孢子菌蛋白并抑制孢子萌发的抗体。(3)我们将确定Bc1a及其结构域的结构。(4)我们将研究外孢子体的基底层的结构和组装，包括 依附于毛发状的午睡。整个计划项目旨在提供对孢子-宿主相互作用的充分了解，从而能够开发新的炭疽病治疗方法。

Bacillus anthracis, the cause of anthrax, has been developed into a weapon of mass destruction by foreign governments and terrorist groups. The recent release of B. anthracis in the United States, with severe consequences, exposed the need for a more effective response to this threat. B. anthracis is used as a weapon largely because it forms highly resistant spores that can be incorporated into explosive weapons and terrorist devices. Spores enter the body through skin abrasions and by ingestion or inhalation and then germinate and grow as vegetative cells. When growth occurs in internal tissues, the host usually dies within several days. Natural strains of B. anthracis are sensitive to common antibiotics; however, large-scale use of these antibiotics to protect against anthrax is logistically difficult and medically dangerous. In addition, antibioticresistant strains may be used in the future. Furthermore, the current vaccine for anthrax has proven problematic. Thus, new strategies are needed to respond to the anthrax threat, and these are likely to require detailed knowledge of the interactions between the mammalian immune system and the outermost surface of the B. anthracis spore - the exosporium. The exosporium serves as the primary interactive site with host defenses, as the source of surface antigens, and as a semi-permeable barrier that excludes antibodies and destructive enzymes. The exosporium consists of a paracrystalline basal layer and an external hair-like nap. Approximately 50% of the mass of the exosporium appears to be proteins, roughly 20 unique species including glycoproteins. Preliminary studies indicate that exosporium proteins play a role in spore virulence. The goal of this project is to determine the content, structure, and function of the external surface of the exosporium. Of primary importance will be the role in virulence of surface-exposed proteins and glycoproteins. Specifically, we will (1) identify these proteins, make mutations that alter them, and examine the effects of the mutations on host-cell interactions and virulence using a mouse model. (2) We will map epitopes on key exosporium proteins, such as the collagen-like protein (BclA) of the hair-like nap, and examine the effects of antibody binding to these epitopes. Of special interest are antibodies that bind exosporium proteins and inhibit spore germination. (3) We will determine the structure of Bc1A and its domains. (4) We will examine the structure and assembly of the basal layer of the exosporium, including the attachment of the hair-like nap. The entire program project is designed to provide sufficient understanding of spore-host interactions to enable the development of new treatments for anthrax.