Metabolic control of the second messenger cyclic diguanylate: implications to intracellular bacterial pathogens
第二信使环二鸟苷酸的代谢控制:对细胞内细菌病原体的影响
基本信息
- 批准号:10055808
- 负责人:
- 金额:$ 23.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-21 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAnabolismBacteriaBehaviorBiological AssayCell physiologyCellsCelluloseCommunitiesCuesDefectDevelopmentEnzymesExtracellular MatrixFluorescenceFosteringGMP synthaseGenesGenetic EpistasisGoalsGrowthHigh-Throughput Nucleotide SequencingInfectionInvestigationLife StyleMapsMediatingMetabolicMetabolic ControlMetabolismMicrobial BiofilmsMusMutationOrganismPathway interactionsPeriodicityPhagocytesPhysiologicalPhysiological AdaptationPlayProductionProtein BiosynthesisProteinsProxyPyruvate KinaseReporterReportingRibosomesRoleSalmonellaSalmonella typhimuriumSecond Messenger SystemsSignal TransductionSignaling MoleculeTestingTranslational ActivationVirulenceacute infectioncell motilitydiguanylate cyclaseenvironmental changeenzyme activityexperiencegenetic analysismacrophagemetabolomicsmutantnovelpathogenpathogenic bacteriaphosphoric diester hydrolase
项目摘要
PROJECT SUMMARY
Bacteria exist as single cells in a planktonic state, but they also associate into
multicellular communities known as biofilms. A rise in the intracellular levels of the
second messenger cyclic diguanylate (c-di-GMP) promotes biofilm formation in a wide
range of bacterial species. Thus, understanding the control of c-di-GMP levels is
essential to comprehend the transition between planktonic to biofilm states. Bacteria
harbor diguanylate cyclases and phosphodiesterases, which are enzymes that
synthesize and degrade c-di-GMP, respectively. A given bacterial species often harbors
a large repertoire of these enzymes, each regulating a distinct cellular process. We
reported that a Salmonella enterica serovar Typhimurium strain lacking the mgtC
virulence gene harbors increased levels of c-di-GMP and of cellulose, a major
component of biofilms that inhibits Salmonella replication inside macrophages. We have
now identified the specific diguanylate cyclases responsible for the c-di-GMP-
dependent cellulose synthesis in the mgtC mutant and established that they undergo
post-translational activation. We have also utilized a novel c-di-GMP fluorescence
reporter to select mutations (currently being mapped by high-throughput sequencing)
that affect the activities of these diguanylate cyclases. This proposal seeks to define
how the identified diguanylate cyclases are activated, and to determine the role of
MgtC in controlling crucial physiological functions in Salmonella during infection.
Specifically, the identification of genes controlling these diguanylate cyclases will
enable us to explore how these enzymes are controlled during Salmonella replication
inside macrophages and, by proxy, make testable inferences about metabolic changes
promoted by MgtC. These investigations will reveal the cues promoting c-di-GMP
synthesis and biofilm formation, and how bacterial pathogens must control their
metabolism to replicate in host phagocytic cells.
项目概要
细菌以浮游状态的单细胞形式存在,但它们也结合成
称为生物膜的多细胞群落。细胞内的水平升高
第二信使环二鸟苷酸 (c-di-GMP) 广泛促进生物膜形成
细菌种类的范围。因此,了解 c-di-GMP 水平的控制是
对于理解浮游状态到生物膜状态之间的转变至关重要。细菌
含有二鸟苷酸环化酶和磷酸二酯酶,这些酶
分别合成和降解c-di-GMP。特定的细菌种类通常含有
这些酶的大量组成部分,每种酶都调节着不同的细胞过程。我们
报道称,肠沙门氏菌鼠伤寒血清型菌株缺乏 mgtC
毒力基因含有增加水平的 c-di-GMP 和纤维素,这是一种主要的
抑制巨噬细胞内沙门氏菌复制的生物膜成分。我们有
现在确定了负责 c-di-GMP- 的特定二鸟苷酸环化酶
mgtC 突变体中依赖的纤维素合成,并确定它们经历
翻译后激活。我们还利用了一种新型 c-di-GMP 荧光
记者选择突变(目前正在通过高通量测序进行定位)
影响这些二鸟苷酸环化酶的活性。该提案旨在定义
确定的二鸟苷酸环化酶是如何被激活的,并确定其作用
MgtC 在感染期间控制沙门氏菌的关键生理功能。
具体来说,控制这些二鸟苷酸环化酶的基因的鉴定将
使我们能够探索沙门氏菌复制过程中如何控制这些酶
在巨噬细胞内部,并通过代理对代谢变化做出可测试的推论
由 MgtC 推动。这些调查将揭示促进 c-di-GMP 的线索
合成和生物膜形成,以及细菌病原体必须如何控制它们
代谢在宿主吞噬细胞中复制。
项目成果
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