Functional Genetic Analysis of Klebsiella pneumoniae Hypervirulence
肺炎克雷伯菌高毒力的功能遗传分析
基本信息
- 批准号:10450624
- 负责人:
- 金额:$ 10.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-15 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AsiaAttenuatedClinicalCommunity-Acquired InfectionsDataDevelopmentDiagnosisDiagnosticDiagnostic ProcedureDiseaseDissociationEncapsulatedExhibitsGenesGenomeGoalsGrowthHealthHospitalsHumanIn VitroIndividualInfectionKlebsiella pneumoniaeKnowledgeLibrariesLinkMedicalModelingMolecularMorbidity - disease rateMulti-Drug ResistanceNosocomial InfectionsOutcomeOutcome StudyPathogenesisPathway interactionsPersonal CommunicationPhenotypePneumoniaProductionReportingResearchRoleRouteSepticemiaSolidSurfaceTestingTherapeuticUrinary tract infectionUrineVirulencebasecapsulecarbapenem resistancecellular targetingcombatdesignepidemiologic dataexperimental studyfitnessfunctional genomicsgenetic analysisimprovedmortalitymouse modelmutantnew therapeutic targetnovelpathogenprogramsresistant straintherapeutic targettool
项目摘要
Project Summary
Klebsiella pneumoniae is one of the most common nosocomial pathogens and is typically associated with
urinary tract infections (UTIs), pneumonia, and septicemia. Two lineages of K. pneumoniae have emerged from
classical strains that challenge the successful treatment of these infections. One lineage includes hypervirulent
strains causing invasive community-acquired infections and the other encompasses carbapenem-resistant (CR)
isolates, primarily causing multi-drug resistant UTIs; the transfer of CR to hypervirulent strains is a real and
imminent threat as evidenced by the emergence of such strains in Asia. Infections caused by either lineage have
greater morbidity and mortality. Hypervirulent strains often exhibit a hypermucoviscous (hmv) phenotype evident
when bacterial colonies are pulled off a surface form a long, adherent string. Typically, hmv K. pneumoniae
expresses K1 or K2 capsule type and if capsule is ablated the strain becomes non-mucoid and avirulent. The
supposition that capsule and hypermucoidy are inextricably linked to hypervirulence is tenuous as UTI isolates
are often non-mucoid, encapsulated and infectious; moreover, some reports have identified strains that are
encapsulated but avirulent, non-encapsulated but hypermucoid, or hypervirulent but non-mucoid. These
observations identify a major gap in our understanding of the molecular mechanisms that control
hypermucoviscosity and how it influences K. pneumoniae pathogenesis. Preliminary data suggests that hmv
strains phenotypically switch to non-mucoid when grown in human urine, without loss of capsule. We have
capitalized on this groundbreaking phenotype to identify genes that, when disrupted, restore hmv in urine or
suppress hmv under standard culture conditions. This proposal will use these mutants as a tool to identify
capsule-independent mechanisms that control mucoidy and delineate how hmv distinctly influences K.
pneumoniae uropathogenesis versus invasive disease. We hypothesize that capsule and mucoidy are linked,
but non-synonymous, and that each distinctly influences K. pneumoniae via different infectious routes.
Experiments proposed in Aim 1 will investigate the roles of capsule and mucoidy during primary pneumonia and
dissemination, identifying capsule-dependent and -independent genes that control mucoidy and their individual
contribution to invasive infection. Studies in Aim 2 will evaluate the functional role of mucoidy and capsule during
UTI using a model hmv K. pneumoniae strain and two clinical UTI isolates. The successful execution of this
proposal will deepen our understanding of the cellular factors that drive mucoidy and capsule, and dissect their
contribution to invasive infections versus UTIs. The identification of these cellular factors may provide novel
targets for therapeutics and diagnostics, improving our ability to diagnose and treat the most challenging K.
pneumoniae infections.
项目摘要
肺炎克雷伯菌是医院内最常见的病原体之一,通常与
尿路感染(UTIs)、肺炎和败血症。肺炎克雷伯菌的两个谱系已经从
挑战这些感染的成功治疗的经典菌株。一种血统包括超强毒力
引起侵袭性社区获得性感染的菌株和另一种包括碳青霉烯耐药(CR)的菌株
主要引起多重耐药的尿路感染;CR向超强毒力菌株的转移是真正和
迫在眉睫的威胁从亚洲出现的这种紧张局势中可见一斑。由任何一种血统引起的感染
更高的发病率和死亡率。超强毒株通常表现出明显的高粘性(HMV)表型。
当细菌菌落从表面上拉出时,就会形成一根长的粘附线。典型的HMV肺炎克雷伯菌
表达K1或K2囊型,如果囊型被消融,菌株变得非粘液性和无毒。这个
假设包膜和高粘液性与超强毒力有千丝万缕的联系是站不住脚的,因为UTI分离株
通常是非粘液性、包裹性和传染性的;此外,一些报告已经确定了
包膜但无毒,无包膜但高粘液,或高毒力但非粘液。这些
观察发现,我们对控制的分子机制的理解存在重大差距
高黏度及其对肺炎克雷伯菌致病机制的影响。初步数据显示,HMV
当菌株在人尿液中生长时,表型转换为非粘液型,不会丢失被膜。我们有
利用这种突破性的表型来识别基因,当被干扰时,恢复尿液中的HMV或
在标准培养条件下抑制HMV。这项提议将使用这些突变体作为一种工具来识别
控制粘液体和描述HMV如何明显影响K。
肺炎尿路病原学与侵袭性疾病。我们假设胶囊和粘液是有联系的,
但不是同义词,而且每一种都通过不同的感染途径影响肺炎克雷伯菌。
目标1中提出的实验将研究胶囊和黏液样物质在原发性肺炎和
传播,识别控制粘液体及其个体的被膜依赖和独立基因
对侵袭性感染的贡献。目标2的研究将评估黏液样物质和胶囊在
UTI使用模式HMV肺炎克雷伯菌株和两个临床UTI分离株。成功地执行了这项任务
该提案将加深我们对驱动粘液样变和包膜的细胞因素的理解,并剖析其
与尿路感染相比,对侵袭性感染的贡献。对这些细胞因子的鉴定可能会提供新的
治疗和诊断的目标,提高我们诊断和治疗最具挑战性的K。
肺炎感染。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Characterization of Klebsiella pneumoniae Extracellular Polysaccharides.
肺炎克雷伯菌胞外多糖的表征。
- DOI:10.1002/cpz1.937
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Khadka,Saroj;Ring,BrookeE;Pariseau,DrewA;Mike,LauraA
- 通讯作者:Mike,LauraA
Genetic Manipulation of Klebsiella pneumoniae.
肺炎克雷伯菌的基因操作。
- DOI:10.1002/cpz1.912
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Ring,BrookeE;Khadka,Saroj;Pariseau,DrewA;Mike,LauraA
- 通讯作者:Mike,LauraA
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Laura Anzaldi Mike其他文献
Laura Anzaldi Mike的其他文献
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{{ truncateString('Laura Anzaldi Mike', 18)}}的其他基金
Control of Klebsiella capsule biosynthesis and attachment
克雷伯菌荚膜生物合成和附着的控制
- 批准号:
10713888 - 财政年份:2023
- 资助金额:
$ 10.74万 - 项目类别:
Functional Genetic Analysis of Klebsiella pneumoniae Hypervirulence
肺炎克雷伯菌高毒力的功能遗传分析
- 批准号:
9789465 - 财政年份:2021
- 资助金额:
$ 10.74万 - 项目类别:
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