The Role of TamAB in Salmonella Pathogenesis
TamAB 在沙门氏菌发病机制中的作用
基本信息
- 批准号:10415194
- 负责人:
- 金额:$ 22.67万
- 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:2021-06-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAttenuatedBacteriaBiochemicalCell Membrane PermeabilityCellsComplexDataDefectDiseaseEnvironmentFutureGammaproteobacteriaGenesGeneticGoalsGrowthHeat shock proteinsHomologous GeneImmuneImmune systemIn VitroInfectionLifeMass Spectrum AnalysisMembraneMembrane ProteinsMolecularMonitorMusMutationNaturePathogenesisPhagosomesPhenotypeProteinsRegulationRegulonResearchRoleSalmonellaSalmonella entericaSalmonella infectionsSalmonella typhimuriumStressSuppressor MutationsSystemVancomycinVirulenceVirulence Factorsantimicrobialbeta barrelbiological adaptation to stresscombatfoodbornefoodborne pathogenimprovedmacrophagemembermembrane assemblymutantpathogenic bacteriatissue culturetranslocase
项目摘要
ABSTRACT
Salmonella Typhimurium is a major food-borne pathogen that propagates within macrophages,
leading to life-threatening disease. The long-term objectives of our research are to understand the
molecular mechanisms by which Salmonella circumvents the host immune system to cause disease.
The outer membrane of the bacterium is the interface with the immune system. Outer membrane beta-
barrel proteins are normally assembled by the Bam complex. A homolog of Bam, the TamAB
translocation module is highly conserved in the Gammaproteobacteria. Originally proposed as a system
for assembly of a subset of beta-barrel proteins, the so-called autotransporter proteins, the actual
function of TamAB is unknown. We have discovered that tamAB is a previously unrecognized member
of the PhoPQ regulon and is induced when Salmonella is replicating in macrophages, suggesting that
this system is important for virulence. Indeed, our preliminary data strongly support our primary
hypothesis that TamAB is induced to assist Bam function under the stressful conditions in the
phagosome. Our secondary hypothesis is that TamAB is required for proper assembly of
particular proteins in the outer membrane under the conditions in the phagosome, and that
decreases or loss of these proteins attenuate Salmonella virulence. In Aim 1, we will determine
outer membrane composition using mass spectrometry, and monitor expression of envelope stress
response systems, to determine the biochemical and regulatory effects caused by loss of TamAB,
thereby identifying proteins that directly or indirectly require TamAB for proper assembly. We will also
isolate mutations that suppress in vitro defects in outer membrane permeability conferred or
exacerbated by loss of TamAB. In Aim 2, we will characterize identified loci and their role in
macrophage survival and virulence. The overall role of the identified factors in macrophage survival
will be revealed by genetic interactions with tamAB. Understanding the roles of TamAB will inform us
about the conditions in the phagosome leading to outer membrane assembly stress and the
mechanisms used by Salmonella to combat them. Identifying the specific proteins affected by loss of
TamAB also identifies additional virulence factors critical for Salmonella pathogenesis.
摘要
鼠伤寒沙门氏菌是一种主要的食源性病原体,在巨噬细胞内繁殖,
导致危及生命的疾病。我们研究的长期目标是了解
沙门氏菌绕过宿主免疫系统致病的分子机制。
细菌的外膜是免疫系统的界面。外膜β-
桶蛋白通常由Bam复合体组装。Bam的同源物,TamAB
易位模块在变形杆菌中高度保守。最初是作为一个系统提出的
为了组装贝塔桶蛋白的子集,所谓的自动转运蛋白,实际的
TamAB的功能尚不清楚。我们发现TamAB是一个以前未被识别的成员
并在沙门氏菌在巨噬细胞中复制时被诱导,表明
这一系统对毒力很重要。事实上,我们的初步数据有力地支持了我们的初选
在应激条件下,TamAB被诱导辅助Bam功能的假说
噬菌体。我们的第二个假设是TamAB是正确组装
在吞噬小体中的条件下,外膜中的特定蛋白质,以及
这些蛋白质的减少或丢失会减弱沙门氏菌的毒力。在目标1中,我们将确定
外膜成分使用质谱仪,并监测包膜应力的表达
反应系统,以确定TamAB丢失引起的生化和调节效应,
从而识别直接或间接需要TamAB才能正确组装的蛋白质。我们还将
分离在体外抑制外膜通透性缺陷的突变
失去TamAB加剧了这一局面。在目标2中,我们将描述已识别的基因座及其在
巨噬细胞的存活和毒力。已确定的因素在巨噬细胞存活中的总体作用
将通过与TamAB的遗传相互作用来揭示。了解TamAB的角色将为我们提供信息
关于吞噬体内导致外膜装配应力的条件和
沙门氏菌用来对抗它们的机制。确定受基因缺失影响的特定蛋白质
TamAB还确定了对沙门氏菌致病至关重要的其他毒力因子。
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)
Interplay between Rho, H-NS, spurious transcription, and Salmonella gene regulation.
- DOI:10.1073/pnas.2211222119
- 发表时间:2022-08-16
- 期刊:
- 影响因子:11.1
- 作者:
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JAMES M. SLAUCH其他文献
JAMES M. SLAUCH的其他文献
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{{ truncateString('JAMES M. SLAUCH', 18)}}的其他基金
Regulation of the Salmonella Pathogenicity Island 1 Type III Secretion System via the hilD 3' untranslated region
通过 hilD 3 非翻译区调节沙门氏菌致病性岛 1 III 型分泌系统
- 批准号:
10625450 - 财政年份:2022
- 资助金额:
$ 22.67万 - 项目类别:
Regulation of the Salmonella Pathogenicity Island 1 Type III Secretion System via the hilD 3' untranslated region
通过 hilD 3 非翻译区调节沙门氏菌致病性岛 1 III 型分泌系统
- 批准号:
10527931 - 财政年份:2022
- 资助金额:
$ 22.67万 - 项目类别:
The Role of TamAB in Salmonella Pathogenesis
TamAB 在沙门氏菌发病机制中的作用
- 批准号:
10287293 - 财政年份:2021
- 资助金额:
$ 22.67万 - 项目类别:
Characterizing the targets of phagocytic superoxide in Salmonella
沙门氏菌吞噬超氧化物靶标的表征
- 批准号:
9083232 - 财政年份:2016
- 资助金额:
$ 22.67万 - 项目类别:
Integration of Small RNAs in Control of Salmonella Pathogenicity Island 1
小RNA整合控制沙门氏菌致病性岛1
- 批准号:
9321026 - 财政年份:2016
- 资助金额:
$ 22.67万 - 项目类别:
Regulation of the Salmonella Pathogenicity Island 1 Type III Secretion System
沙门氏菌致病性岛1型III型分泌系统的调控
- 批准号:
8111309 - 财政年份:2010
- 资助金额:
$ 22.67万 - 项目类别:
Regulation of the Salmonella Pathogenicity Island 1 Type III Secretion System
沙门氏菌致病性岛1型III型分泌系统的调控
- 批准号:
8490284 - 财政年份:2010
- 资助金额:
$ 22.67万 - 项目类别:
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