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

基本信息

  • 批准号:
    10671542
  • 负责人:
  • 金额:
    $ 18.94万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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 莱姆病的病原体,伯氏疏螺旋体,是一种螺旋体细菌, 美国最常见的节肢动物感染每年莱姆病都会导致 流行地区的患者以及治疗后患者的发病率很高 莱姆病综合征B。burgdorferi被认为是一种细胞外病原体,因此,必须 与宿主反应抗衡,在主动的先天性和适应性免疫面前定居和坚持。 先前的研究表明,模拟哺乳动物感染的条件诱导表达 BosR/RpoN/RpoS调节的毒力相关B。burgdorferi基因,包括ospC、dbpBA和 bbk32.除了这些基因之外,已经鉴定了其他协同调节的基因座,但是 它们编码的蛋白质没有已知的功能。包括斯卡雷和霍克实验室在内的许多研究小组, 专注于表面暴露的蛋白质,以确定它们如何与宿主结构相互作用, B的致病潜力。burgdorferi。确定功能的一个限制是缺乏同源性, 这些疏螺旋体蛋白与来自其它病原体的毒力相关蛋白共有。的缺乏 这些表面暴露的蛋白质如何有助于B的建立和维持的信息。 伯氏螺旋体的传染性和发病机制在目前的知识基础中代表了一个显著的空白。一 符合该描述的疏螺旋体基因/蛋白是bbk 53/BBK 53及其旁系同源物。初步数据 本文所呈现的结果表明,重组BBK 53结合人杀皮素(hDCD),一种阴离子杀皮素, 由皮肤成纤维细胞产生的抗菌肽。随后,斯卡雷和霍克团体 发现B.相对于其同基因亲本,缺乏bbk 53的burgdorferi对hDCD更敏感, 补体菌株。这些结果表明,B. burgdorferi BBK 53与hDCD结合,并阻止 这种致命的肽整合到疏螺旋体膜,最值得注意的是能量化的细胞质 膜,从而减少这些螺旋体在皮肤内初始感染期间的先天杀伤。这 假设将被测试与以下具体目标:(1)表征之间的相互作用 BBK 53::hDCD和hDCD衍生物;和(2)确定BBK 53是否提供hDCD依赖性存活 对B有利。在体外感染后的伯氏螺旋体。这里描述的BBK 53的作用是重要的, 它代表了对B观察到的第一个阴离子抗微生物肽抗性机制。burgdorferi。作为 这样,BBK 53可以减少B先天清除。burgdorferi,促进皮肤的定植,并提供 一个更大的螺旋体池,随后传播到更深的组织中。

项目成果

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JON T SKARE其他文献

JON T SKARE的其他文献

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{{ truncateString('JON T SKARE', 18)}}的其他基金

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:
    10425475
  • 财政年份:
    2022
  • 资助金额:
    $ 18.94万
  • 项目类别:
An Intracellular Niche for Borrelia burgdorferi
伯氏疏螺旋体的细胞内生态位
  • 批准号:
    8438390
  • 财政年份:
    2012
  • 资助金额:
    $ 18.94万
  • 项目类别:
An Intracellular Niche for Borrelia burgdorferi
伯氏疏螺旋体的细胞内生态位
  • 批准号:
    8300386
  • 财政年份:
    2012
  • 资助金额:
    $ 18.94万
  • 项目类别:
Host Spirochete Interactions in Lyme Disease
莱姆病中宿主螺旋体的相互作用
  • 批准号:
    7613339
  • 财政年份:
    2006
  • 资助金额:
    $ 18.94万
  • 项目类别:
Host Spirochete Interactions in Lyme Disease
莱姆病中宿主螺旋体的相互作用
  • 批准号:
    7188606
  • 财政年份:
    2006
  • 资助金额:
    $ 18.94万
  • 项目类别:
Host Spirochete Interactions in Lyme Disease
莱姆病中宿主螺旋体的相互作用
  • 批准号:
    7030116
  • 财政年份:
    2006
  • 资助金额:
    $ 18.94万
  • 项目类别:
Host Spirochete Interactions in Lyme Disease
莱姆病中宿主螺旋体的相互作用
  • 批准号:
    7774393
  • 财政年份:
    2006
  • 资助金额:
    $ 18.94万
  • 项目类别:
Host Spirochete Interactions in Lyme Disease
莱姆病中宿主螺旋体的相互作用
  • 批准号:
    7389512
  • 财政年份:
    2006
  • 资助金额:
    $ 18.94万
  • 项目类别:
VIRULENCE ASSOCIATED PROTEINS OF BORRELIA BURGDORFERI
伯氏疏螺旋体毒力相关蛋白
  • 批准号:
    6170668
  • 财政年份:
    1999
  • 资助金额:
    $ 18.94万
  • 项目类别:
Genetic Mechanisms in Borrelia burgdorferi Pathogenesis
伯氏疏螺旋体发病机制的遗传机制
  • 批准号:
    7589384
  • 财政年份:
    1999
  • 资助金额:
    $ 18.94万
  • 项目类别:

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