Leptospira interrogans Len adhesins

描述（由申请人提供）：钩端螺旋体病由问号钩端螺旋体及其近亲引起，是一种重要的人畜共患病，影响美国和世界许多其他地区的人类。这些细菌通过穿透粘膜或结膜，或通过皮肤的破裂感染人类和其他动物。然后细菌通过血液传播到整个宿主，然后侵入其他组织。人类钩端螺旋体病可导致一系列使人衰弱的症状，并经常导致死亡。了解钩端螺旋体能够启动和建立感染的机制可以指导改进诊断和预防/治疗疗法的发展。 感染性钩端螺旋体对其宿主补体介导的杀伤替代途径具有很强的抵抗力。我们的研究发现L.问号线虫可以将宿主补体调节因子H结合到其外表面，这是许多其他病原体为避免被宿主补体杀死而采用的策略。在感染过程中，L.问号螺旋体侵入并定殖肾脏和其他宿主器官，这显然是由螺旋体与宿主细胞外基质（ECM）组分相互作用的能力促进的。我们发现L.问号线虫携带六个独立但相似的基因，每个基因编码一种可以结合H因子和/或ECM蛋白的蛋白质。所有六种钩端螺旋体蛋白与哺乳动物内皮抑制素具有预测的结构和一些功能相似性，并被命名为LenA、LenB、LenC、LenD、LenE和LenF（Len =钩端螺旋体内皮抑制素样蛋白）。我们假设Len蛋白使L.在一些实施方案中，所述抗体能够抵抗宿主补体的杀伤并与宿主ECM相互作用。作为我们的中心假设的推论，我们预测，所有感染性钩端螺旋体产生一个或多个Len蛋白，以促进哺乳动物感染，感染的人类和其他动物产生抗体对这些Len蛋白。为了验证我们的假设，我们将（1）进行Len蛋白和它们的宿主配体之间的相互作用的功能表征和（2）评估使用Len蛋白用于钩端螺旋体病患者的血清学诊断的实用性。 公共卫生相关性：钩端螺旋体病的病原体，问号钩端螺旋体和该属的密切相关的成员，是高度侵入性的病原体，可以建立免疫活性个体的持续感染。本项目的目的是表征一个家族的六个钩端螺旋体蛋白，我们发现与人类免疫系统调节剂和细胞外基质成分相互作用，因此可能在人类钩端螺旋体病中发挥重要作用。

DESCRIPTION (provided by applicant): Leptospirosis, caused by the spirochete Leptospira interrogans and close relatives of that genus, is a significant zoonotic disease affecting humans throughout the United Sates and many other parts of the world. These bacteria infect humans and other animals by penetrating mucous membranes or conjunctiva, or through breaks in the skin. Bacteria then disseminate throughout the host via the bloodstream, followed by invasion of other tissues. Leptospirosis in humans can lead to a range of debilitating symptoms, and, not infrequently, death. Understanding the mechanisms by which leptospires are able to initiate and establish infection can direct development of improved diagnostics and preventative/treatment therapies. Infectious leptospires are very resistant to their hosts' alternative pathway of complement-mediated killing. Our studies found that L. interrogans can bind the host complement regulator factor H to its outer surface, a strategy adopted by many other pathogens to avoid killing by host complement. During infection, L. interrogans invades and colonizes kidneys and other host organs, apparently facilitated by the spirochete's abilities to interact with host extracellular matrix (ECM) components. We discovered that L. interrogans carries six separate but similar genes, each of which encodes a protein that can bind factor H and/or ECM proteins. All six leptospiral proteins share predicted structural and some functional similarities with mammalian endostatin, and have been designated LenA, LenB, LenC, LenD, LenE and LenF (Len = Leptospiral ENdostatin-like protein). We hypothesize that Len proteins enable L. interrogans to both resist killing by host complement and to interact with host ECM. As a corollary to our central hypothesis, we predict that all infectious leptospires produce one or more Len proteins to facilitate mammalian infection, and that infected humans and other animals produce antibodies against those Len proteins. To test our hypothesis, we will (1) perform functional characterization of interactions between Len proteins and their host ligands and (2) evaluate the practicality of using Len proteins for serological diagnosis of leptospirosis patients. PUBLIC HEALTH RELEVANCE: The causative agents of leptospirosis, Leptospira interrogans and closely-related members of that genus, are highly invasive pathogens that can establish persistent infections of immunocompetent individuals. The aim of this project is to characterize a family of six leptospiral proteins we found to interact with human immune system regulators and extracellular matrix components, and may therefore play important roles in human leptospirosis.