A novel antimicrobial resistance mechanism for Borrelia burgdorferi

伯氏疏螺旋体的新型抗菌药物耐药机制

• 批准号: 10671542
• 负责人: JON T SKARE
• 金额: $ 18.94万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10671542
• 关键词: Address; Affect; Antibiotic Therapy; Antimicrobial Cationic Peptides; Antimicrobial Resistance; Area; Arthropods; Bacteria; Bacteria sigma factor KatF protein; Binding; Binding Proteins; Biochemical; Bite; Borrelia; Borrelia burgdorferi; Borrelia oxidative stress regulator; Cell Line; Cell membrane; Cells; Complement; Data; Databases; Dermal; Dermis; Diagnosis; Environment; Etiology; Family member; Fibroblasts; Foundations; Genes; Growth; Homologous Gene; Human; Immune; Immune response; In Vitro; Incubated; Infection; Innate Immune Response; Ixodes; Knock-in; Knowledge; Length; Life Cycle Stages; Ligands; Locales; Lyme Disease; Maintenance; Mammals; Mediating; Membrane; Membrane Proteins; Methods; Morbidity - disease rate; Natural Immunity; Order Spirochaetales; OspC protein; Parents; Pathogenesis; Pathogenicity; Patients; Peptides; Persons; Poison; Post Treatment Lyme Disease Syndrome; Predisposition; Production; Property; Proteins; Recombinants; Reporting; Role; Seminal; Skin; Skin colonization; Structure; Surface; Surface Plasmon Resonance; System; Testing; Time; Tissues; United States; Vertebrates; Virulence; Work; adaptive immune response; adaptive immunity; antimicrobial peptide; cell killing; dermcidin; enzootic; extracellular; gain of function; immune clearance; insight; intercalation; interest; knowledge base; mutant; novel; pathogen; permissiveness; prevent; protein function; resistance mechanism; tick feeding; tick transmission; transmission process

PROJECT SUMMARY The etiologic agent of Lyme disease, Borreliella burgdorferi, is a spirochetal bacterium that represents the most common arthropod-based infection in the United States. Each year Lyme disease contributes to significant morbidity in patients within endemic areas as well as for those who suffer from post treatment Lyme disease syndrome. B. burgdorferi is considered an extracellular pathogen and, as such, must contend with the host response to colonize and persist in the face of active innate and adaptive immunity. Prior studies demonstrated that conditions mimicking mammalian infection induce the expression of BosR/RpoN/RpoS-regulated virulence associated B. burgdorferi genes, including ospC, dbpBA, and bbk32. In addition to these genes, other loci that are coordinately regulated have been identified but the proteins they encode have no known function(s). Many groups, including the Skare and Höök labs, have focused on surface exposed proteins to determine how they interface with host structures to promote the pathogenic potential of B. burgdorferi. One limitation in determining function is the lack of homology that these borrelial proteins share with virulence associated proteins from other pathogens. The dearth of information of how these surface exposed proteins contribute to the establishment and maintenance of B. burgdorferi infectivity and pathogenesis represents a significant gap in the current knowledge base. One such borrelial gene/protein that fits this description is bbk53/BBK53 and its paralogues. Preliminary data presented herein indicates that recombinant BBK53 binds to human dermcidin (hDCD), an anionic antimicrobial peptide that is produced by dermal fibroblasts. Subsequently, the Skare and Höök groups found that B. burgdorferi lacking bbk53 were more sensitive to hDCD relative to its isogenic parent and complement strains. These results suggest that B. burgdorferi BBK53 binds to hDCD and prevents the integration of this lethal peptide into borrelial membranes, most notably the energized cytoplasmic membrane, and thus reduces innate killing of these spirochetes during initial infection within the skin. This hypothesis will be tested with the following Specific Aims: (1) Characterize the interactions between BBK53::hDCD and hDCD derivatives; and (2) Determine if BBK53 provides an hDCD-dependent survival advantage to B. burgdorferi following in vitro infection. The role described here for BBK53 is significant as it represents the first anionic antimicrobial peptide resistance mechanism observed for B. burgdorferi. As such, BBK53 may reduce innate clearance of B. burgdorferi, promote colonization of the skin, and provide a larger pool of spirochetes for subsequent dissemination into deeper tissues.

项目摘要 莱姆病的病因学药物Borreliella burgdorferi是一种代表 在美国，最常见的基于节肢动物的感染。每年莱姆病都会有助于 内在区域内的患者以及患有治疗后的患者的发病率很高 莱姆病综合征。 B. burgdorferi被认为是细胞外病原体，因此必须 与主动的天生和适应性免疫学面对殖民和持续存在的宿主反应。 先前的研究表明，模仿哺乳动物感染的条件引起了 BOSR/RPON/RPOS调节病毒相关的B. burgdorferi基因，包括OSPC，DBPBA和 BBK32。除这些基因外，还确定了其他协调调节的局部局部 它们编码的蛋白质没有已知功能。包括Skare和Höök实验室在内的许多团体都有 专注于表面暴露的蛋白质，以确定它们如何与宿主结构接口以促进 B. burgdorferi的致病潜力。确定功能的一个局限性是缺乏同源性 这些侧质蛋白与其他病原体的病毒相关蛋白共享。死亡 这些表面暴露蛋白如何有助于建立和维护的信息。 Burgdorferi感染和发病机理代表了当前知识库中的一个显着差距。一 适合此描述的这种杂质基因/蛋白质是BBK53/BBK53及其副群。初步数据 本文提出的表明重组BBK53与人类皮肤素（HDCD）结合，一种阴离子 由真皮成纤维细胞产生的抗菌肽。随后，Skare和Höök组 发现缺乏BBK53的B. burgdorferi对HDCD相对于其同源性父母更敏感 补充菌株。这些结果表明，B. burgdorferi BBK53与HDCD结合并防止 将这种致命肽的整合到疏松膜中，最著名的是通电的细胞质 膜，从而减少了皮肤最初感染期间这些螺旋体的先天杀戮。这 假设将以以下特定目的进行检验：（1）表征 BBK53 :: HDCD和HDCD衍生物； （2）确定BBK53是否提供HDCD依赖性生存 在体外感染后，B. burgdorferi的优势。此处描述的BBK53的角色很重要，因为 它代表了伯氏芽孢杆菌观察到的第一个阴离子抗菌胡椒耐药机制。作为 这样的BBK53可能会降低B. burgdorferi的先天清除，促进皮肤定殖，并提供 较大的螺旋体池，随后将其传播到更深的组织中。