Molecular Assembly on the Cell Surface of Actinomyces
放线菌细胞表面的分子组装
基本信息
- 批准号:10455056
- 负责人:
- 金额:$ 39.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-02-19 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:ActinomycesActinomycetalesAdhesivesArginineBacterial AdhesinsBindingBiochemical GeneticsBiologicalCandidiasisCell WallCell surfaceComplexCrystallizationDefectDentalDental EnamelDental PlaqueDevelopmentDiseaseEconomic BurdenElectronsElementsEnzymesGene ClusterGeneticGingivitisGlycoproteinsGoalsGram-Positive BacteriaGrantHomeostasisHomologous GeneHousekeepingHumanInvestigationLinkMediatingMembraneMembrane ProteinsMicrobial BiofilmsMicroscopicMolecular MimicryMutationNamesNatureOdontogenesisOral cavityPathway interactionsPeptide Signal SequencesPeriodontitisPharmaceutical PreparationsPilumPlayPopulationPositioning AttributeProcessPropertyProteinsResearchResolutionRoleSignal TransductionStructureSurfaceTestingTwin Multiple BirthVaccinesage groupaggregation factorbaseeffective therapyglycosylationinhibitorinsightmanmicrobial communitymolecular assembly/self assemblymutantnoveloral biofilmoral streptococcipathogenpreventpublic health relevancesortasetooth surface
项目摘要
PROJECT SUMMARY
Dental plaque represents one of the most complex microbial communities or biofilms known to afflict man. Oral
biofilm-related diseases, e.g. dental carries, gingivitis, periodontitis, and candidosis, impact a large population of
all age groups and continue to impose a huge economic burden due to the lack of effective therapies. The
development of dental plaque begins with the attachment of early bacterial colonizers to the tooth enamel,
generating an adhesive matrix that then attracts intermediate and late colonizers. Actinomyces spp. are key early
colonizers that play a prominent role in biofilm development by virtue of their ability to directly interact not only
with the tooth surface but also with a number of both early and intermediate colonizers. Therefore, our studies
have focused on dissecting the adhesive properties, i.e. fimbriae and non-fimbrial proteins, dictating these
interactions and the mechanism of their assembly on the surface of Actinomyces oris – the most abundant
Actinomyces in the human oral cavity. During the past grant period, we identified the major co-aggregation factor
named CafA, which mediates A. oris interaction with oral streptococci. Remarkably, CafA is found at the tip of a
distinct fimbrial structure made of the pilus shaft FimA, although cafA is not genetically linked to the type 2 fimbrial
gene cluster fimB-fimA-srtC2. Significantly, we found that spatial positioning of the pilus tip adhesin CafA is
essential for CafA-mediated bacterial coaggregation and this process requires the housekeeping sortase SrtA.
We also discovered a small membrane protein named SafA, conserved in the Actinomycetales order, which is
critical for SrtA membrane association. Investigations into the essential nature of srtA revealed the convergence
of two conserved pathways, SrtA-catalyzed cell wall anchoring and LytR-CpsA-Psr (LCP)-mediated
glycosylation, on the cell wall anchored glycoprotein GspA, itself critical for A. oris formation of mono- and multi-
species biofilms and membrane integrity. Thus, we propose that SrtA is the fulcrum for molecular assembly on
the cell surface of Actinomyces. Using biochemical, genetic electron microscopic, and structural approaches, we
aim to test this central hypothesis by examining the mechanism of pilus hijacking and polymicrobial interactions
mediated by the major co-aggregation factor CafA in A. oris, elucidating the mechanism of SrtA modulation of
CafA spatial positioning and CafA-mediated coaggregation, and examining the glycosylation mechanism of the
cell wall anchored GspA that contributes to biofilm formation and membrane integrity. The conservation of
sortase-mediated surface assembly in Gram-positive bacteria and the utilization of srtA essentiality for inhibitor
screens in other Gram-positive pathogens thus magnify the significance of our studies on how sortase SrtA
modulates polymicrobial interactions via surface display of adhesive factors.
项目总结
牙菌斑是已知的困扰人类的最复杂的微生物群落或生物膜之一。口头的
与生物被膜有关的疾病,如携带牙齿、牙周炎、牙周炎和念珠菌病,影响着大量的
由于缺乏有效的治疗方法,所有年龄段的儿童都会受到伤害,并继续造成巨大的经济负担。这个
牙菌斑的形成始于早期细菌定殖物附着到牙釉质上,
产生一种粘性基质,然后吸引中晚期殖民者。放线菌属是关键的提早
在生物膜发展中发挥突出作用的殖民者,凭借它们直接相互作用的能力,不仅
与牙齿表面,但也与一些早期和中期殖民者。因此,我们的研究
专注于分析粘附性,即菌毛和非菌毛蛋白,决定了这些
最丰富的放线菌表面的相互作用及其组装机制
人类口腔中的放线菌。在过去的赠款期间,我们确定了主要的共同聚集因素
名为CAFA,它介导口蹄疫杆菌与口腔链球菌的相互作用。值得注意的是,CAFA被发现在一个
由菌毛柄FIMA构成的独特的菌毛结构,尽管CAFA与2型菌毛没有遗传联系
基因簇FIMB-FIMA-srtC2。值得注意的是,我们发现毛端粘附素CAFA的空间位置是
对于CAFA介导的细菌共聚集是必不可少的,这一过程需要管家分类酶srtA。
我们还发现了一种名为SafA的小分子膜蛋白,它在放线菌目中保守,是
对srtA膜结合至关重要。对srtA本质的研究揭示了这种趋同
两条保守的途径:srtA催化的细胞壁锚定和LytR-CPSA-PSR(LCP)介导的
糖基化作用,在细胞壁上锚定的糖蛋白GSPA,本身对口蹄疫形成单一和多个...
物种生物膜和膜的完整性。因此,我们认为srtA是分子组装的支点。
放线菌的细胞表面。使用生化、遗传电子显微镜和结构方法,我们
目的通过研究菌毛劫持和多菌体相互作用的机制来验证这一中心假说
由主要的共聚集因子CAFA介导,阐明了srtA调控的机制
CAFA的空间定位和CAFA介导的共聚集,并研究了糖基化机制
细胞壁锚定的GSPA有助于生物膜的形成和膜的完整性。自然资源的保护
葡萄糖酶介导的革兰氏阳性菌表面组装及srtA在抑制物中的应用
因此,在其他革兰氏阳性病原体中进行筛查,放大了我们对Sortase srtA如何
通过黏附因子的表面展示来调节多个微生物的相互作用。
项目成果
期刊论文数量(40)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Role of the Emp Pilus Subunits of Enterococcus faecium in Biofilm Formation, Adherence to Host Extracellular Matrix Components, and Experimental Infection.
屎肠球菌 Emp 菌毛亚基在生物膜形成、宿主细胞外基质成分粘附和实验感染中的作用。
- DOI:10.1128/iai.01396-15
- 发表时间:2016
- 期刊:
- 影响因子:3.1
- 作者:Montealegre,MariaCamila;Singh,KavindraV;Somarajan,SudhaR;Yadav,Puja;Chang,Chungyu;Spencer,Robert;Sillanpää,Jouko;Ton-That,Hung;Murray,BarbaraE
- 通讯作者:Murray,BarbaraE
Forward Genetic Dissection of Biofilm Development by Fusobacterium nucleatum: Novel Functions of Cell Division Proteins FtsX and EnvC.
- DOI:10.1128/mbio.00360-18
- 发表时间:2018-04-24
- 期刊:
- 影响因子:6.4
- 作者:Wu C;Al Mamun AAM;Luong TT;Hu B;Gu J;Lee JH;D'Amore M;Das A;Ton-That H
- 通讯作者:Ton-That H
Lethality of sortase depletion in Actinomyces oris caused by excessive membrane accumulation of a surface glycoprotein.
表面糖蛋白的过度膜积聚引起的放线菌分子酶耗竭的致死性。
- DOI:10.1111/mmi.12780
- 发表时间:2014-12
- 期刊:
- 影响因子:3.6
- 作者:Wu C;Huang IH;Chang C;Reardon-Robinson ME;Das A;Ton-That H
- 通讯作者:Ton-That H
Structural determinants of Actinomyces sortase SrtC2 required for membrane localization and assembly of type 2 fimbriae for interbacterial coaggregation and oral biofilm formation.
放线菌分选酶 SrtC2 的结构决定因素是膜定位和 2 型菌毛组装所需的,以实现细菌间共聚集和口腔生物膜形成。
- DOI:10.1128/jb.00093-12
- 发表时间:2012
- 期刊:
- 影响因子:3.2
- 作者:Wu,Chenggang;Mishra,Arunima;Reardon,MelissaE;Huang,I-Hsiu;Counts,SarahC;Das,Asis;Ton-That,Hung
- 通讯作者:Ton-That,Hung
The Actinomyces oris type 2 fimbrial shaft FimA mediates co-aggregation with oral streptococci, adherence to red blood cells and biofilm development.
- DOI:10.1111/j.1365-2958.2010.07252.x
- 发表时间:2010-08
- 期刊:
- 影响因子:3.6
- 作者:Mishra A;Wu C;Yang J;Cisar JO;Das A;Ton-That H
- 通讯作者:Ton-That H
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{{ truncateString('Hung Ton-That', 18)}}的其他基金
Metabolic modulation of Fusobacterium nucleatum virulence
具核梭杆菌毒力的代谢调节
- 批准号:
10681729 - 财政年份:2023
- 资助金额:
$ 39.76万 - 项目类别:
UCLA Dentist-Scientist and Oral Health-Researcher Training Program
加州大学洛杉矶分校牙医科学家和口腔健康研究员培训计划
- 批准号:
10440483 - 财政年份:2021
- 资助金额:
$ 39.76万 - 项目类别:
UCLA Dentist-Scientist and Oral Health-Researcher Training Program
加州大学洛杉矶分校牙医科学家和口腔健康研究员培训计划
- 批准号:
10270286 - 财政年份:2021
- 资助金额:
$ 39.76万 - 项目类别:
UCLA Dentist-Scientist and Oral Health-Researcher Training Program
加州大学洛杉矶分校牙医科学家和口腔健康研究员培训计划
- 批准号:
10440538 - 财政年份:2021
- 资助金额:
$ 39.76万 - 项目类别:
UCLA Dentist-Scientist and Oral Health-Researcher Training Program
加州大学洛杉矶分校牙医科学家和口腔健康研究员培训计划
- 批准号:
10655274 - 财政年份:2021
- 资助金额:
$ 39.76万 - 项目类别:
UCLA Dentist-Scientist and Oral Health-Researcher Training Program
加州大学洛杉矶分校牙医科学家和口腔健康研究员培训计划
- 批准号:
10655434 - 财政年份:2021
- 资助金额:
$ 39.76万 - 项目类别:
UCLA Dentist-Scientist and Oral Health-Researcher Training Program
加州大学洛杉矶分校牙医科学家和口腔健康研究员培训计划
- 批准号:
10414189 - 财政年份:2021
- 资助金额:
$ 39.76万 - 项目类别:
Virulence determinants of Fusobacterium nucleatum
具核梭杆菌的毒力决定因素
- 批准号:
10221250 - 财政年份:2018
- 资助金额:
$ 39.76万 - 项目类别:
Virulence determinants of Fusobacterium nucleatum
具核梭杆菌的毒力决定因素
- 批准号:
9982064 - 财政年份:2018
- 资助金额:
$ 39.76万 - 项目类别:
Virulence determinants of Fusobacterium nucleatum
具核梭杆菌的毒力决定因素
- 批准号:
10454482 - 财政年份:2018
- 资助金额:
$ 39.76万 - 项目类别:
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肺部先天免疫和放线菌目的病原体
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7787847 - 财政年份:2010
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- 批准号:
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- 资助金额:
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