Borrelia burgdorferi BBK32 Inhibits the Classical Pathway by Blocking Activation of the C1 Complement Complex.
Borrelia burgdorferi BBK32 Inhibits the Classical Pathway by Blocking Activation of the C1 Complement Complex.
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DOI：
10.1371/journal.ppat.1005404
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发表时间：
2016-01
期刊：
影响因子：
6.7
通讯作者：
Skare JT
中科院分区：
文献类型：
--
作者：
Garcia BL;Zhi H;Wager B;Höök M;Skare JT
运输血液、体液或间质液的病原体必须采取策略来逃避先天免疫防御，特别是补体系统。通过募集补体的宿主调节剂到其表面，许多病原体能够逃避补体介导的攻击。莱姆病螺旋体（Borrelia burgdorferi）产生许多与H因子相关分子结合的表面蛋白，其作为补体旁路途径的显性负调节剂起作用。关于B是如何形成的，我们知道的相对较少。尽管观察到一些广义菌株对经典途径活化敏感，但Burgdorferi避开了经典补体途径。在这里，我们报告说，疏螺旋脂蛋白BBK 32有效地和特异性地抑制经典的途径，结合高亲和力的起始补体C1复合物。此外，B.在其表面上产生BBK 32的伯氏细胞结合C1和C1 r以及B的血清敏感衍生物。通过经典途径以BBK 32依赖性方式保护伯氏螺旋体免于被杀死。随后的生物化学和生物物理方法将BBK 32的抗补体活性定位于其球状C末端结构域。机理研究表明，BBK 32的作用是通过结合和抑制C1亚组分C1 r（其作为经典途径的起始丝氨酸蛋白酶），将C1截留在其酶原形式中。据我们所知，这是螺旋体蛋白作为经典途径的直接抑制剂的第一份报告，也是能够特异性和非共价抑制C1/C1 r的生物分子的唯一例子。通过确定一种独特的补体逃避模式，这项研究大大提高了我们对病原体如何破坏和潜在操纵宿主先天免疫系统的理解。人类补体系统是一个连接的血液蛋白网络，能够识别和消除微生物入侵者。为了避免补体激活的破坏力，许多进入血流的微生物表达通过与特定补体组分相互作用而破坏补体级联的关键步骤的分子。在这项研究中，我们表明，莱姆病的病原体，伯氏疏螺旋体，表达一种称为BBK 32的表面蛋白，该蛋白靶向并抑制补体的第一组分，命名为C1。在与人C1结合后，BBK 32将补体经典途径的这种起始蛋白酶复合物捕获在非活性状态，并阻止该途径的下游蛋白水解事件。我们的研究定义了一种新的机制，通过这种机制，微生物能够逃脱人类先天免疫系统，并将补体蛋白酶C1 r鉴定为细菌抗补体分子的一种以前未知的靶标。因此，疏螺旋体蛋白BBK 32的补体抑制活性的发现显著地推进了我们对致病细菌如何在免疫活性宿主中存活的理解。
Pathogens that traffic in blood, lymphatics, or interstitial fluids must adopt strategies to evade innate immune defenses, notably the complement system. Through recruitment of host regulators of complement to their surface, many pathogens are able to escape complement-mediated attack. The Lyme disease spirochete, Borrelia burgdorferi, produces a number of surface proteins that bind to factor H related molecules, which function as the dominant negative regulator of the alternative pathway of complement. Relatively less is known about how B. burgdorferi evades the classical pathway of complement despite the observation that some sensu lato strains are sensitive to classical pathway activation. Here we report that the borrelial lipoprotein BBK32 potently and specifically inhibits the classical pathway by binding with high affinity to the initiating C1 complex of complement. In addition, B. burgdorferi cells that produce BBK32 on their surface bind to both C1 and C1r and a serum sensitive derivative of B. burgdorferi is protected from killing via the classical pathway in a BBK32-dependent manner. Subsequent biochemical and biophysical approaches localized the anti-complement activity of BBK32 to its globular C-terminal domain. Mechanistic studies reveal that BBK32 acts by entrapping C1 in its zymogen form by binding and inhibiting the C1 subcomponent, C1r, which serves as the initiating serine protease of the classical pathway. To our knowledge this is the first report of a spirochetal protein acting as a direct inhibitor of the classical pathway and is the only example of a biomolecule capable of specifically and noncovalently inhibiting C1/C1r. By identifying a unique mode of complement evasion this study greatly enhances our understanding of how pathogens subvert and potentially manipulate host innate immune systems. The human complement system is a connected network of blood proteins capable of recognizing and eliminating microbial intruders. To avoid the destructive force of complement activation, many microorganisms that enter the bloodstream express molecules that disrupt key steps of the complement cascade by interacting with specific complement components. In this study we show that the causative agent of Lyme disease, Borrelia burgdorferi, expresses a surface-protein termed BBK32 that targets and inhibits the first component of complement, designated C1. Upon binding to human C1, BBK32 traps this initiating protease complex of the classical pathway of complement in an inactive state, and prevents the downstream proteolytic events of the pathway. Our study defines a new mechanism by which microbes are able to escape the human innate immune system and identifies complement protease C1r as a previously unknown target of bacterial anti-complement molecules. Thus, discovery of the complement inhibitory activity of the borrelial protein BBK32 significantly advances our understanding of how disease-causing bacteria survive in immune competent hosts.