Intracellular Invasion by Streptococcus mutans: Significance in Disease
变形链球菌的细胞内侵袭:在疾病中的意义
基本信息
- 批准号:9024352
- 负责人:
- 金额:$ 36.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-05-17 至 2018-03-31
- 项目状态:已结题
- 来源:
- 关键词:Active ImmunizationAdhesionsAntibodiesArterial Fatty StreakAtherosclerosisAttenuatedBacteriaBindingBinding ProteinsBiological MarkersBlood CirculationBlood PlateletsBrain hemorrhageCardiacCerebrumClinicalCollagenCommunicable DiseasesCoronary arteryCytoplasmDataDefectDentalDental cariesDetectionDevelopmentDiseaseEndocarditisEndothelial CellsEndotheliumEnvironmental Risk FactorEventExtracellular MatrixGenesGenomic DNAGlycoproteinsGoalsHealthHeartHeart DiseasesHeart ValvesHumanImmunoblot AnalysisIn VitroInfectionInfective endocarditisInvadedLamininLarvaLesionLinkMediatingMicrobial BiofilmsModelingMolecularMusMutagenesisNamesOperonOral cavityOrganismOryctolagus cuniculusPathogenesisPatientsPhenotypePlatelet ActivationPrevention strategyPreventive treatmentPropertyProphylactic treatmentProteinsPublicationsPublishingRecombinantsResearchRiskRoleSiteStreptococcus mutansSurfaceSystemSystemic infectionThreonineTissuesTranslatingVariantVirulenceVirulence FactorsWorkantimicrobialdesignefficacy testingexperienceglycosylationglycosyltransferasehuman tissuein vitro Modelin vivomutantnoveloral bacteriaoral infectionpathogenpreventresearch studytrait
项目摘要
DESCRIPTION (provided by applicant): There is growing evidence that certain facets of heart disease may be influenced by infections arising from the oral cavity. Streptococcus mutans, a major etiologic agent of dental caries, is also a leading causative agent of infective endocarditis
(IE) and has been implicated in the development and progression of atherosclerosis. We have recently demonstrated that certain S. mutans strains invade and persist in the cytoplasm of Human Coronary Artery Endothelial Cells (HCAEC). Invasion of HCAEC was associated with an ability to avidly bind to collagen and laminin, and invasive strains were significantly more virulet than non-invasive strains in the Galleria mellonella model for systemic infection. A collagen-binding protein (Cnm) was found only in invasive strains, and inactivation of the cnm gene significantly impaired collagen and laminin binding capacity, abolished HCAEC invasion, and attenuated virulence in G. mellonella. Characterization of a gene encoding a putative glycosyltransferase (CsbB) co-transcribed with cnm suggested that CsbB is involved in Cnm glycosylation. Preliminary data using a rabbit endocarditis model suggested that expression of Cnm enables infection of the underlying endothelium by S. mutans whereas a cnm mutant was trapped in the heart valve vegetation. Collectively, our data suggest that the ability to invade an persist in the host cytoplasm is an important, previously unrecognized, virulence trait of S. mutans. Our working hypothesis is that S. mutans strains expressing Cnm have an enhanced capacity to colonize human tissues, and that this ability is a major virulence trait in systemic infections. The major goals of this application are to conduct the functional analysis of Cnm and to characterize the role of Cnm in host-bacteria interactions. To achieve these goals, we propose three well-integrated Specific Aims. In Aim 1 (Molecular characterization of the cnm locus), we will (i) conduct the transcriptional characterization of the cnm operon, (ii) employ mutagenesis approaches to continue the characterization of the Cnm and CsbB, and (iii) identify the essential machinery for intracellular invasion using an heterologous host system. In Aim 2 (Functional analysis of Cnm), we will (i) use recombinant variant forms of Cnm to identify the functional domains of Cnm, and (ii) determine whether Cnm is glycosylated and, if so, how Cnm is modified. In Aim 3 (Streptococcus mutans-host interactions), we will (i) use in vitro models to assess Cnm-platelet interactions, (ii) use an ex vivo adhesion model to examine the ability of invasive and non-invasive strains to colonize heart tissues, and (iii) use a rabbit endocarditis model to establish the contribution of Cnm to the pathogenesis of IE and to test the efficacy of active immunization with Cnm to prevent S. mutans infections. This study has strong potential to be readily translated into clinical settings as Cnm could serve as a biomarker for detection of hypervirulent strains in patients in need to receive prophylactic treatment, or as a potential target for the development of effective strategies for prevention and treatment of S. mutans extra-oral infections.
描述(由申请人提供):越来越多的证据表明,心脏病的某些方面可能受到口腔感染的影响。变形链球菌是龋病的主要病原体,也是感染性心内膜炎的主要病原体
(IE)并且与动脉粥样硬化的发展和进展有关。我们最近证明了某些S。变异株侵入并持续存在于人冠状动脉内皮细胞(HCAEC)的细胞质中。HCAEC的侵袭与与胶原蛋白和层粘连蛋白结合的能力相关,并且在用于全身感染的大蜡螟模型中,侵袭性菌株比非侵袭性菌株具有更明显的病毒性。胶原结合蛋白(Cnm)仅在侵袭性菌株中发现,cnm基因的失活显著削弱了胶原和层粘连蛋白的结合能力,消除了HCAEC的侵袭性,并减弱了G.梅隆内拉编码与cnm共转录的推定糖基转移酶(CsbB)的基因的表征表明CsbB参与Cnm糖基化。使用兔心内膜炎模型的初步数据表明,Cnm的表达使S.而cnm突变体被捕获在心脏瓣膜赘生物中。总的来说,我们的数据表明,侵入宿主细胞质的能力是一个重要的,以前没有认识到的,毒力性状的S。变异人我们的工作假设是S.表达Cnm的变异株具有增强的定殖人类组织的能力,并且这种能力是全身感染中的主要毒力性状。该应用程序的主要目标是进行Cnm的功能分析,并表征Cnm在宿主-细菌相互作用中的作用。为了实现这些目标,我们提出了三个整合良好的具体目标。在目标1(cnm基因座的分子表征)中,我们将(i)进行cnm操纵子的转录表征,(ii)采用诱变方法继续表征Cnm和CsbB,以及(iii)使用异源宿主系统鉴定细胞内入侵的基本机制。在目标2(Cnm的功能分析)中,我们将(i)使用Cnm的重组变体形式来鉴定Cnm的功能结构域,以及(ii)确定Cnm是否被糖基化,如果是,Cnm如何被修饰。在目标3(变形链球菌-宿主相互作用)中,我们将(i)使用体外模型评估Cnm-血小板相互作用,(ii)使用离体粘附模型检查侵袭性和非侵袭性菌株定植心脏组织的能力,(iii)使用兔心内膜炎模型确定Cnm对IE发病机制的贡献,并测试Cnm主动免疫预防S.变形杆菌感染这项研究具有很强的潜力,可以很容易地转化为临床环境,因为Cnm可以作为一种生物标志物,用于检测需要接受预防性治疗的患者中的高毒力菌株,或者作为一个潜在的目标,用于预防和治疗S.口腔外变形菌感染
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)
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Jacqueline Abranches其他文献
Jacqueline Abranches的其他文献
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{{ truncateString('Jacqueline Abranches', 18)}}的其他基金
Intracellular Invasion by Streptococcus mutans: Significance in Disease
变形链球菌的细胞内侵袭:在疾病中的意义
- 批准号:
8436799 - 财政年份:2013
- 资助金额:
$ 36.05万 - 项目类别:
Intracellular Invasion by Streptococcus mutans: Significance in Disease
变形链球菌的细胞内侵袭:在疾病中的意义
- 批准号:
10415992 - 财政年份:2013
- 资助金额:
$ 36.05万 - 项目类别:
Association of CBP+ Streptococcus mutans with root caries in older adults
CBP 变形链球菌与老年人根龋的关联
- 批准号:
10401604 - 财政年份:2013
- 资助金额:
$ 36.05万 - 项目类别:
Intracellular Invasion by Streptococcus mutans: Significance in Disease
变形链球菌的细胞内侵袭:在疾病中的意义
- 批准号:
10624268 - 财政年份:2013
- 资助金额:
$ 36.05万 - 项目类别:
Intracellular Invasion by Streptococcus mutans: Significance in Disease
变形链球菌的细胞内侵袭:在疾病中的意义
- 批准号:
9170784 - 财政年份:2013
- 资助金额:
$ 36.05万 - 项目类别:
Intracellular Invasion by Streptococcus mutans: Significance in Disease
变形链球菌的细胞内侵袭:在疾病中的意义
- 批准号:
8663216 - 财政年份:2013
- 资助金额:
$ 36.05万 - 项目类别:
Intracellular Invasion by Streptococcus mutans: Significance in Disease
变形链球菌的细胞内侵袭:在疾病中的意义
- 批准号:
9236181 - 财政年份:2013
- 资助金额:
$ 36.05万 - 项目类别:
Intracellular Invasion by Streptococcus mutans: Significance in Disease
变形链球菌的细胞内侵袭:在疾病中的意义
- 批准号:
10177997 - 财政年份:2013
- 资助金额:
$ 36.05万 - 项目类别:
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