BBA57-Mediated Borrelial Persistence, Genesis of Inflammation and Immunity

 描述（由申请人提供）：莱姆病是一种在美国、欧洲和亚洲部分地区流行的病媒传播疾病，由细菌病原体伯氏疏螺旋体引起。这种感染很难诊断，目前还没有人类疫苗。该应用程序将研究BBA 57-一种独特的疏螺旋体基因产物和新鉴定的未知功能的毒力决定因素-如何有助于微生物感染性和发病机制的多个方面，并评估其在产生保护性宿主免疫力方面的功效。虽然许多细菌病原体已经进化出限制宿主杀微生物反应的措施，但对B如何产生杀微生物反应知之甚少。伯氏螺旋体在传播给哺乳动物宿主时逃避先天免疫。基于我们已发表的和新的初步数据，我们假设BBA 57，一种体内诱导的，表面暴露的外膜蛋白，促进螺旋体防御特定的宿主先天免疫反应，并且抗原诱导关节细胞中的趋化因子的产生，从而引发关节炎。在成功完成拟议的工作后，我们将能够证明，据我们所知，BBA 57代表了B的第一个例子。一种赋予特异性抗菌肽（AMP）抗性的伯氏螺旋体蛋白，从而促进早期B的建立。鼠宿主中的伯氏螺旋体感染。我们有三个主要目标。首先，我们将研究如何BBA 57有助于螺旋体AMP耐药在早期感染。其次，我们将确定关节细胞类型，负责BBA 57介导的趋化因子反应，对关节炎至关重要。最后，由于BBA 57也在蜱中大量产生，我们将探索该蛋白在维持疏螺旋体生命周期的载体阶段中的作用，包括蜱-小鼠传播，并根据我们的初步免疫数据，我们将评估其作为产生保护性宿主免疫的新候选抗原的潜力。总之，这些研究将有助于更好地了解B的感染性和发病机制。并帮助开发新的预防和治疗措施，以对抗感染。

 DESCRIPTION (provided by applicant): Lyme borreliosis is a prevalent vector-borne disease in the United States, Europe, and parts of Asia, caused by the bacterial pathogen Borrelia burgdorferi. The infection can be difficult to diagnose, and a human vaccine is currently unavailable. The application will study how BBA57 - a unique borrelial gene product and newly identified virulence determinant of unknown function - contributes to multiple aspects of microbial infectivity and pathogenesis and also assess its efficacy in generating protective host immunity against infection. Although many bacterial pathogens have evolved measures to limit host microbicidal responses, relatively little is known about how B. burgdorferi evade innate immunity as they transmit to mammalian hosts. Based on our published and new preliminary data, we hypothesize that BBA57, an in-vivo induced, surface-exposed outer membrane protein, facilitates spirochete defense against specific host innate immune responses and that the antigen induces production of neutrophil-recruiting chemokines in joint cells, which triggers arthritis. Upon successful completion of the proposed work, we will be able to demonstrate that BBA57 represents, to the best of our knowledge, the first example of a B. burgdorferi protein that confers resistance to specific antimicrobial peptides (AMPs), thereby promoting establishment of early B. burgdorferi infection in murine hosts. We have three major goals. First, we will examine how BBA57 contributes to spirochete AMP resistance during early infection. Second, we will identify the joint cell type(s) that are responsible for BBA57-mediated chemokine responses critical for arthritis. Finally, as BBA57 is also dramatically produced in ticks, we will explore the role of the protein in perpetuating the vector phases of the borrelial lfe cycle, including tick-to-mouse transmission, and based on our preliminary immunization data, we will assess its potential as a new candidate antigen for generation of protective host immunity. In sum, these studies will contribute to better understanding the infectivity and pathogenesis of B. burgdorferi and help in the development of novel preventive and therapeutic measures to combat infection.