BBA57-Mediated Borrelial Persistence, Genesis of Inflammation and Immunity

 描述(申请人提供)：莱姆疏螺旋体病是一种流行的媒介传播疾病，在美国、欧洲和亚洲部分地区，由细菌病原体伯氏疏螺旋体引起。这种感染可能很难诊断，目前还无法获得人类疫苗。这项应用将研究BBA57-一种独特的脆性基因产物和新发现的未知功能的毒力决定因素-如何在微生物感染性和发病机制的多个方面做出贡献，并评估其在产生针对感染的保护性宿主免疫方面的有效性。尽管许多细菌病原体已经进化出限制宿主杀菌反应的措施，但相对较少的人知道伯氏杆菌在传播给哺乳动物宿主时如何逃避先天免疫。根据我们已发表的和新的初步数据，我们假设BBA57是一种体内诱导的、暴露在表面的外膜蛋白，有助于螺旋体防御特定宿主的先天性免疫反应，并且该抗原诱导关节细胞产生中性粒细胞募集趋化因子，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，BBA57是第一个对特定抗菌肽(AMPs)具有抗药性的伯氏杆菌蛋白，从而促进在小鼠宿主中建立早期伯氏杆菌感染。我们有三个主要目标。首先，我们将研究BBA57如何在早期感染期间对螺旋体AMP耐药做出贡献。其次，我们将确定负责BBA57介导的趋化因子反应的关节细胞类型(S)，这些细胞对关节炎至关重要。最后，由于BBA57也在硬体中戏剧性地产生，我们将探索该蛋白在延续丝状病毒LFe周期的媒介阶段中的作用，包括从硬体到小鼠的传播，并基于我们的初步免疫数据，我们将评估它作为一种新的候选抗原产生保护性宿主免疫的潜力。总之，这些研究将有助于更好地了解伯氏杆菌的传染性和发病机制，并有助于开发新的预防和治疗措施来对抗感染。

 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.