Phage resistance and mobile genetic elements in Vibrio cholerae
霍乱弧菌的噬菌体抗性和移动遗传元件
基本信息
- 批准号:10366735
- 负责人:
- 金额:$ 47.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-27 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AreaBacterial ChromosomesBacteriophagesBiochemicalBiological ModelsCapsidCellsCholeraChromosomesClustered Regularly Interspaced Short Palindromic RepeatsComplexCryoelectron MicroscopyDNA biosynthesisDataDefense MechanismsDiseaseDisease OutbreaksDisease OutcomeEcosystemElectron MicroscopyElementsEnsureEnvironmentEpidemicEvolutionExcisionGene ExpressionGenesGeneticGenetic MaterialsGenomeGenomicsGoalsHumanInfectionInfection ControlInfrastructureIslandLyticMeasuresMediatingMobile Genetic ElementsModificationMolecularNatureOpen Reading FramesOutcomeParasitesPredatory BehaviorProcessProductionProteomicsReceptor CellRegulationResistanceRoleSanitationSmall RNAStructureSystemTailTechniquesTranscriptUntranslated RNAVibrio choleraeVirionWaterWorkbaseclinically relevantdriving forcegene productglobal healthimprovedinhibitor/antagonistmicrobialnovelpathogenpathogenic bacteriaresponsetargeted nucleasestransmission processwaterborne pathogen
项目摘要
Waterborne pathogens like Vibrio cholerae pose significant threats to global health. V. cholerae can persist in
the aquatic environment, and it can emerge to cause devastating cholera outbreaks in endemic regions and
vulnerable areas lacking adequate water and sanitation infrastructure. The host-pathogen interactions that
dictate disease outcome and cholera transmission dynamics occur in the context of a complex microbial
ecosystem that includes predatory bacterial viruses (phages). Phages profoundly impact the evolution of their
bacterial hosts, both through predation, which selects for hosts with defenses that overcome phage killing and
through mobilization and dissemination of genetic material. Certain mobile elements called the phage satellites
have evolved sophisticated mechanisms to exploit phages for their own selfish spread. Such elements interfere
with the replication of the phages they parasitize, and as such, provide their cellular hosts with a means to limit
phage predation. Our lab discovered PLEs (for phage-inducible chromosomal island-like elements) in V.
cholerae that provide specific and robust defense against ICP1, the dominant lytic phage co-circulating with V.
cholerae in cholera endemic regions. Upon infection by ICP1, PLEs excise from the V. cholerae chromosome,
replicate to high copy and are assembled into virions to spread the PLE genome to new cells while
concurrently abolishing phage production. PLEs are uniquely potent, highly specific, anti-phage barriers that
act through multiple mechanisms to ensure that ICP1 does not propagate and spread to neighboring V.
cholerae cells. However, few mechanisms of direct interference with ICP1 are known, and none are essential
for PLE activity, indicating that additional mechanisms await discovery in this system. This proposal builds on
our prior work defining the PLE lifecycle in response to phage infection to gain a mechanistic understanding of
how PLEs execute their unusually potent anti-phage activity. Our data indicate that PLE’s most potent anti-
phage inhibitors are focused on blocking virion assembly. To understand PLE activity in mechanistic detail, we
will pursue the following specific aims: 1) We will define the structural composition of virions and capsid
assembly intermediates for ICP1 and PLE 2) We will Interrogate the functions of three PLE-encoded ORFs that
are each sufficient to inhibit phage 3) We will determine how a PLE-encoded small RNA perturbs phage gene
expression. The proposed studies are expected to reveal novel mechanistic paradigms not previously
documented in phage satellites or other anti-phage defense systems. The long-term coevolution of V. cholerae
PLE and ICP1 serves as a powerful model system to understand clinically relevant phage defense
mechanisms to inform phage therapy efforts and understand the forces driving the evolution of bacterial
pathogens.
霍乱弧菌等水传播病原体对全球健康构成重大威胁。霍乱弧菌可以持续存在
水生环境,它可能会在流行地区和地区造成毁灭性的霍乱疫情
脆弱地区缺乏足够的水和卫生基础设施。宿主与病原体的相互作用
决定疾病结果和霍乱传播动态发生在复杂的微生物环境中
包括掠食性细菌病毒(噬菌体)的生态系统。噬菌体对其进化产生了深远的影响
细菌宿主,通过捕食,选择具有克服噬菌体杀伤和防御能力的宿主
通过遗传物质的动员和传播。某些称为噬菌体卫星的移动元件
已经进化出复杂的机制来利用噬菌体进行自私的传播。这些元素会干扰
随着它们寄生的噬菌体的复制,为它们的细胞宿主提供了一种限制的方法
噬菌体捕食。我们的实验室在 V 中发现了 PLE(噬菌体诱导的染色体岛样元素)。
霍乱弧菌对 ICP1(与霍乱弧菌共同循环的主要裂解噬菌体)提供特异性和强大的防御。
霍乱流行地区的霍乱。 ICP1 感染后,PLE 会从霍乱弧菌染色体上切除,
复制到高拷贝并组装成病毒粒子,将 PLE 基因组传播到新细胞,同时
同时废除噬菌体生产。 PLE 是独特有效、高度特异性的抗噬菌体屏障,
通过多种机制来确保ICP1不会传播和扩散到邻近的V。
霍乱细胞。然而,直接干扰 ICP1 的机制知之甚少,而且没有一个是必要的
对于 PLE 活动,表明该系统中还有其他机制等待发现。该提案建立在
我们之前的工作定义了响应噬菌体感染的 PLE 生命周期,以获得对
PLE 如何执行其异常有效的抗噬菌体活性。我们的数据表明,PLE 最有效的抗
噬菌体抑制剂专注于阻止病毒粒子组装。为了详细了解 PLE 活动,我们
将追求以下具体目标:1)我们将定义病毒体和衣壳的结构组成
ICP1 和 PLE 的组装中间体 2) 我们将询问三个 PLE 编码的 ORF 的功能,这些 ORF
每一个都足以抑制噬菌体 3) 我们将确定 PLE 编码的小 RNA 如何扰乱噬菌体基因
表达。拟议的研究预计将揭示以前没有的新机制范式
记录在噬菌体卫星或其他反噬菌体防御系统中。霍乱弧菌的长期协同进化
PLE 和 ICP1 作为强大的模型系统来了解临床相关的噬菌体防御
为噬菌体治疗工作提供信息并了解驱动细菌进化的力量的机制
病原体。
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)
专利数量(0)
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Kimberley Diane Seed其他文献
Kimberley Diane Seed的其他文献
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{{ truncateString('Kimberley Diane Seed', 18)}}的其他基金
Molecular mechanisms driving the antagonistic coevolution of viral satellites and bacteriophages in Vibrio cholerae
霍乱弧菌病毒卫星和噬菌体拮抗协同进化的分子机制
- 批准号:
10033684 - 财政年份:2020
- 资助金额:
$ 47.65万 - 项目类别:
Molecular mechanisms driving the antagonistic coevolution of viral satellites and bacteriophages in Vibrio cholerae
霍乱弧菌病毒卫星和噬菌体拮抗协同进化的分子机制
- 批准号:
10401451 - 财政年份:2020
- 资助金额:
$ 47.65万 - 项目类别:
Molecular mechanisms driving the antagonistic coevolution of viral satellites and bacteriophages in Vibrio cholerae
霍乱弧菌病毒卫星和噬菌体拮抗协同进化的分子机制
- 批准号:
10176401 - 财政年份:2020
- 资助金额:
$ 47.65万 - 项目类别:
Molecular mechanisms driving the antagonistic coevolution of viral satellites and bacteriophages in Vibrio cholerae
霍乱弧菌病毒卫星和噬菌体拮抗协同进化的分子机制
- 批准号:
10624961 - 财政年份:2020
- 资助金额:
$ 47.65万 - 项目类别:
Phage resistance and mobile genetic elements in Vibrio cholerae
霍乱弧菌的噬菌体抗性和移动遗传元件
- 批准号:
9795616 - 财政年份:2018
- 资助金额:
$ 47.65万 - 项目类别:
Phage resistance and mobile genetic elements in Vibrio cholerae
霍乱弧菌的噬菌体抗性和移动遗传元件
- 批准号:
9754762 - 财政年份:2016
- 资助金额:
$ 47.65万 - 项目类别:
Phage resistance and mobile genetic elements in Vibrio cholerae
霍乱弧菌的噬菌体抗性和移动遗传元件
- 批准号:
10494121 - 财政年份:2016
- 资助金额:
$ 47.65万 - 项目类别:
Phage resistance and mobile genetic elements in Vibrio cholerae
霍乱弧菌的噬菌体抗性和移动遗传元件
- 批准号:
9360091 - 财政年份:2016
- 资助金额:
$ 47.65万 - 项目类别:
Phage resistance and mobile genetic elements in Vibrio cholerae
霍乱弧菌的噬菌体抗性和移动遗传元件
- 批准号:
10682489 - 财政年份:2016
- 资助金额:
$ 47.65万 - 项目类别:
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