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:10425475
- 负责人:
- 金额:$ 22.73万
- 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
- 来源:
- 关键词:AddressAffectAftercareAntibiotic TherapyAntimicrobial Cationic PeptidesAntimicrobial ResistanceAreaArthropodsBacteriaBacteria sigma factor KatF proteinBindingBinding ProteinsBiochemicalBiteBorreliaBorrelia burgdorferiBorrelia oxidative stress regulatorCell LineCell membraneCellsComplementDataDatabasesDermalDermisDiagnosisEnvironmentEtiologyFamily memberFibroblastsFoundationsGene ProteinsGenesGrowthHomologous GeneHumanImmuneImmune responseIn VitroInfectionIxodesKnock-inKnowledgeLengthLigandsLocalesLyme DiseaseMaintenanceMammalsMediatingMembraneMembrane ProteinsMethodsMorbidity - disease rateNatural ImmunityOrder SpirochaetalesOspC proteinParentsPathogenesisPathogenicityPatientsPeptidesPersonsPoisonPredispositionPrimary InfectionProductionPropertyProteinsRecombinantsReportingRoleSeminalSkinSkin colonizationStructureSurfaceSurface Plasmon ResonanceSyndromeSystemTestingTimeTissuesUnited StatesVertebratesVirulenceWorkadaptive immune responseadaptive immunityantimicrobial peptidebasecell killingdermcidinenzooticextracellulargain of functionimmune clearanceinsightintercalationinterestknowledge basemutantnovelpathogenpreventprotein functionresistance mechanismtick feedingtick transmissiontransmission process
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.
项目总结
莱姆病的病原体伯氏疏螺旋体是一种螺旋体细菌,代表
在美国最常见的节肢动物感染。每年莱姆病都会导致
流行区内的患者以及那些在治疗后遭受痛苦的患者的显著发病率
莱姆病综合征。伯氏杆菌被认为是一种胞外病原体,因此必须
面对主动的先天免疫和获得性免疫,抗争宿主的定植反应和持之以恒。
先前的研究表明,模拟哺乳动物感染的条件会诱导
BosR/RpoN/rpos调控的伯氏杆菌毒力相关基因,包括ospC、dbpBA和
Bbk32.除了这些基因外,还发现了其他协同调控的基因座,但
它们编码的蛋白质没有已知的功能(S)。许多组织,包括Skare和Hök实验室,都有
聚焦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,以促进
伯氏杆菌的致病潜力。确定函数的一个限制是缺乏同源性,即
这些丝状病毒蛋白与其他病原体的毒力相关蛋白相同。缺乏……
这些表面暴露的蛋白如何有助于建立和维持B.
伯氏杆菌的传染性和致病机制是当前知识基础中的一个重大空白。一
符合这一描述的这种脆性基因/蛋白是bbk53/bbk53及其类似物。初步数据
结果表明,重组BBK53与阴离子人皮质素(HDCD)结合
由真皮成纤维细胞产生的抗菌肽。随后,斯卡雷和Höök集团
发现缺乏bbk53的伯氏杆菌对HDCD比其同基因亲本更敏感。
补体菌株。这些结果表明,伯氏杆菌BBK53与HDCD结合,并阻止
将这种致命的多肽整合到硼质膜中,最显著的是通电的细胞质
因此,在皮肤内最初感染时,减少了对这些螺旋体的先天杀灭。这
假设将以以下具体目标进行检验:(1)描述
BBK53::HDCD和HDCD衍生物;以及(2)确定BBK53是否提供HDCD依赖的生存
体外感染对伯氏杆菌的优势。这里描述的BBK53的作用非常重要,因为
这代表了首次观察到的伯氏杆菌阴离子抗菌肽耐药机制。AS
这样,BBK53可能会减少伯氏杆菌的天然清除,促进皮肤的定植,并提供
一个更大的螺旋体池,以便随后扩散到更深的组织。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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:
10671542 - 财政年份:2022
- 资助金额:
$ 22.73万 - 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:
$ 22.73万 - 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:
$ 22.73万 - 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:
$ 22.73万 - 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:
$ 22.73万 - 项目类别:
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