Bordetella adenylate cyclase toxin: the role of cell interaction in toxin functio
博德特氏菌腺苷酸环化酶毒素:细胞相互作用在毒素功能中的作用
基本信息
- 批准号:7641818
- 负责人:
- 金额:$ 12.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-01 至 2014-06-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingAdenylate CyclaseAdenylate Cyclase ToxinAffectAgeAnimalsAntibodiesApicalApoptoticAwardBacteriaBacterial ProteinsBacterial ToxinsBasic ScienceBindingBiological AssayBordetellaBordetella pertussisCD11 AntigensCalmodulinCatalytic DomainCell CommunicationCell DeathCell membraneCellsChemicalsChinese Hamster Ovary CellCollaborationsComplementCyclic AMPCytolysisDataDevelopmentDiseaseEnergy TransferEnzymesEpithelialEpithelial CellsEpitheliumErythrocytesFamilyGenerationsHemolysisHumanHybridsITGAM geneIn VitroInfectionInflammatoryIntegrinsIntoxicationInvestigationKnowledgeLearningLightLipid BilayersLipidsLung diseasesMeasurementMeasuresMembraneMentorsMethodsMutationOligosaccharidesPathogenesisPertussisPreventionRelative (related person)Research PersonnelResourcesRespiratory Tract InfectionsRoleScientistSheepSmall Interfering RNAStructureStructure of respiratory epitheliumSurfaceTechniquesTestingToxinUnited StatesUniversitiesUropathogenic E. coliVirginiaVirulence Factorsapical membranebasolateral membranecell typecrosslinkcytokineexperiencein vivointerestmacrophagemembermonolayermutantneutrophilnovelpathogenic bacteriapolypeptidepreventreceptorrespiratory
项目摘要
DESCRIPTION (provided by applicant): The adenylate cyclase toxin (AC toxin) is necessary for disease caused by Bordetella pertussis, which has reemerged in the United States over the last two decades. AC toxin is expressed by seven of eight species of Bordetella which cause respiratory disease in humans and a range of animals. The toxin molecule is a unique hybrid of an adenylate cyclase enzyme and a binding domain homologous to the repeats-in-toxin (RTX) family of pore-forming bacterial protein toxins. AC toxin intoxicates host cells by binding to the cell membrane and translocating its catalytic domain across the lipid-bilayer, resulting in unregulated generation of intracellular cAMP. Prevention of translocation by an antibody to the catalytic domain or by certain mutations will enhance the other major function of the toxin, formation of oligomeric pores which cause lysis of erythrocytes and contribute to non-apoptotic cell death of macrophages. The magnitude of intoxication correlates with the relative surface expression of the (32 integrin, CD11b/CD18, a receptor expressed most abundantly on neutrophils and macrophages; however, the relationship between AC toxin and CD11b/CD18 is not well defined. Our preliminary data show that CD11b/CD18 does not simply increase sensitivity of cells to intoxication, but, when high concentrations of toxin are applied to cells, actually limits intoxication while possibly enhancing oligomer formation. We will investigate the basic mechanisms of the interaction between AC toxin and CD11 b/CD18. The determinants of toxin binding and function may explain a novel finding: cells of an epithelial monolayer are insensitive to intoxication by AC toxin applied to the apical surface, surprising because the toxin can intoxicate all cell types so far tested, and important because the bacterium first encounters these cells upon infection. These studies will shed light upon the mechanism of pore formation by bacterial toxins, and the pathogenesis of disease caused by all Bordetellae. The proposed project will continue my interest in basic science that began at the age of 19. My mentor, Dr. Erik Hewlett, with over 25 years of experience" studying Bordetella pertussis, is a preeminent scientist in the field of bacterial toxins. His emphasis on learning through scientific collaboration will complement my plan for structured coursework. The K08 award, in combination with the resources of my mentor and the University of Virginia, will provide me with the support necessary for my full development as a clinician scientist.
RELEVANCE: AC toxin is expressed by seven of the eight species of Bordetella and is also a member of the RTX family of pore-forming bacterial protein toxins that are produced by other pathogenic bacteria such as uropathogenic Escherichia coli. Here, we will characterize the basic mechanisms of cell binding by AC toxin and show that these mechanisms affect the function of the toxin and determine its role as a virulence factor.
描述(由申请人提供):腺苷酸环化酶毒素(AC毒素)是百日咳博德特氏菌引起的疾病所必需的,百日咳博德特氏菌在过去二十年中在美国重新出现。AC毒素由八种博德特氏菌中的七种表达,这些博德特氏菌引起人类和一系列动物的呼吸道疾病。该毒素分子是腺苷酸环化酶和与成孔细菌蛋白毒素的毒素重复序列(RTX)家族同源的结合结构域的独特杂合物。AC毒素通过与细胞膜结合并使其催化结构域跨脂质双层易位而使宿主细胞中毒,导致细胞内cAMP的不受调节的产生。通过抗体至催化结构域或通过某些突变防止易位将增强毒素的其他主要功能,即形成寡聚孔,其引起红细胞裂解并促成巨噬细胞的非凋亡性细胞死亡。中毒的程度与β 2整合素CD 11b/CD 18的相对表面表达相关,该受体在中性粒细胞和巨噬细胞上表达最丰富;然而,AC毒素和CD 11b/CD 18之间的关系尚未明确。我们的初步数据表明,CD 11b/CD 18并不简单地增加细胞对中毒的敏感性,但当高浓度的毒素应用于细胞时,实际上限制了中毒,同时可能增加寡聚体的形成。我们将探讨AC毒素与CD 11 B/CD 18相互作用的基本机制。毒素结合和功能的决定因素可以解释一个新的发现:上皮单层细胞对应用于顶端表面的AC毒素的中毒不敏感,这是令人惊讶的,因为毒素可以使迄今为止测试的所有细胞类型中毒,并且重要的是因为细菌在感染时首先遇到这些细胞。这些研究将阐明细菌毒素形成孔的机制,以及所有博德特氏菌引起的疾病的发病机制。这个项目将继续我从19岁开始对基础科学的兴趣。我的导师Erik Hewlett博士拥有超过25年的研究百日咳杆菌的经验,是细菌毒素领域的杰出科学家。他强调通过科学合作学习,这将补充我的结构化课程计划。K 08奖,与我的导师和弗吉尼亚大学的资源相结合,将为我作为临床科学家的全面发展提供必要的支持。
相关性:AC毒素由八种博德特氏菌中的七种表达,并且也是由其他病原性细菌(例如尿路致病性大肠杆菌)产生的成孔细菌蛋白毒素的RTX家族的成员。在这里,我们将描述AC毒素细胞结合的基本机制,并表明这些机制影响毒素的功能,并确定其作为毒力因子的作用。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Joshua Clark Eby其他文献
Joshua Clark Eby的其他文献
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{{ truncateString('Joshua Clark Eby', 18)}}的其他基金
Bordetella adenylate cyclase toxin: the role of cell interaction in toxin functio
博德特氏菌腺苷酸环化酶毒素:细胞相互作用在毒素功能中的作用
- 批准号:
8099583 - 财政年份:2009
- 资助金额:
$ 12.98万 - 项目类别:
Bordetella adenylate cyclase toxin: the role of cell interaction in toxin functio
博德特氏菌腺苷酸环化酶毒素:细胞相互作用在毒素功能中的作用
- 批准号:
8289635 - 财政年份:2009
- 资助金额:
$ 12.98万 - 项目类别:
Bordetella adenylate cyclase toxin: the role of cell interaction in toxin functio
博德特氏菌腺苷酸环化酶毒素:细胞相互作用在毒素功能中的作用
- 批准号:
8486374 - 财政年份:2009
- 资助金额:
$ 12.98万 - 项目类别:
Bordetella adenylate cyclase toxin: the role of cell interaction in toxin functio
博德特氏菌腺苷酸环化酶毒素:细胞相互作用在毒素功能中的作用
- 批准号:
7767697 - 财政年份:2009
- 资助金额:
$ 12.98万 - 项目类别:
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