Outer membrane proteins of Borrelia burgdorferi

描述（由申请人提供）：莱姆病是全球主要的公共卫生问题，是美国最常见的节肢动物感染。伯氏疏螺旋体（Borrelia burgdorferi）是北美莱姆病的病因，是一种细胞外病原体，具有独特的逃避宿主免疫反应并感染个体数年至数十年的能力。为了更好地了解这种生物是如何在受感染的哺乳动物体内持续存在的，许多实验室，包括我们自己的实验室，都专注于鉴定和表征伯氏疏螺旋体的外表面蛋白质。由于伯氏疏螺旋体与其哺乳动物宿主之间的界面是其外表面，因此位于外膜的蛋白质在传播、毒力、组织趋向性以及最终的免疫逃避中必须发挥重要作用。在过去的资助期内，我们已经确定并重点研究了伯氏疏螺旋体的几种外表面脂蛋白（Osps）。我们已经确定了许多表面脂蛋白在发病机制中的作用，并研究了它们作为候选疫苗的潜力。虽然我们继续在表征表面脂蛋白能够结合因子H来帮助螺旋体方面非常有成效

DESCRIPTION (provided by applicant): Lyme disease is a major public health problem worldwide and is the most common arthropod- borne infection in the United States. Borrelia burgdorferi, which is the cause of Lyme disease in North America, is an extracellular pathogen that has the unique ability to evade the host immune response and infect individuals for years to decades. To gain a better understanding of how this organism persists in the infected mammal, many laboratories, including our own, have focused on identifying and characterizing outer surface proteins of B. burgdorferi. Since the interface between B. burgdorferi and its mammalian host is its outer surface, proteins localized in the outer membrane must play an important role in dissemination, virulence, tissue tropism, and, ultimately, immune evasion. Over the last funding period, we have identified and focused on several outer surface lipoproteins (Osps) from B. burgdorferi. We have determined the role of numerous surface lipoproteins in pathogenesis and examined their potential as vaccine candidates. While we continue to be very productive in characterizing surface lipoproteins that are capable of binding factor H to help aid the spirochete in evading serum-mediated killing during the acute stage of infection, we have yet to identify a specific lipoprotein that could work as a potential vaccine candidate for Lyme disease. The lack of good vaccine efficacy for the various lipoproteins we have been characterizing over the last funding period prompted us to start identifying integral, membrane spanning, outer membrane proteins (OMPs) that could be used as more viable potential vaccine candidates for Lyme disease. These more recent studies also led us to discover the protein machinery required for chaperoning and assembling OMPs into the B. burgdorferi outer membrane. Although the mechanism of outer membrane biogenesis is poorly understood in spirochetes, our recent studies have indicated that a heterooligomeric OM protein beta-barrel assembly machine (BAM) complex is required for proper assembly of OMPs into the borrelial OM. The B. burgdorferi BAM complex is made up of the integral outer membrane protein BamA, and two additional periplasmic lipoproteins located in the inner leaflet of the outer membrane, BB0324 and BB0028. We have shown that the borrelial BAM complex is required for inserting OMPs into the borrelial outer membrane. The studies we propose in this revised, renewal application will allow us to characterize the BAM complex and examine in detail its role in export and translocation of OMPs to the surface of this spirochetal pathogen. A better understanding of the basic mechanisms by which the BAM complex chaperones and exports OMPs to the surface of B. burgdorferi will also allow us, for the first time, to begin elucidating the complete outer surface integral OMP content of B. burgdorferi. Additionally, since the BAM system is a conserved pathway for OMP export and localization among all Gram-negative bacteria, the studies outlined here could lead to the development of novel antibacterial compounds that could have an impact not only against pathogenic spirochetes such as B. burgdorferi and Treponema pallidum, but could potentially be widely applicable against other important human pathogens, such as E. coli, Salmonella, Vibrio, Pseudomonas, Neisseria, Helicobacter and others. PUBLIC HEALTH RELEVANCE: Our long-term goal is to characterize the Borrelia burgdorferi outer surface protein export machine, which we recently discovered. These initial mechanistic studies will allow us to then identify novel outer membrane proteins and other potential mechanisms that could be used to generate a new vaccine or disease modulating therapeutic for Lyme disease. Given that the integral outer membrane protein export machine we will be examining in B. burgdorferi is conserved, at some level, among all proteobacteria, our studies also could greatly benefit public health worldwide by identifying novel broad-spectrum antibacterials that could be used to treat many different devastating and important diseases in the United States and abroad.