Remodeling of intracellular membrane traffic by Brucella effectors

布鲁氏菌效应器对细胞内膜交通的重塑

基本信息

  • 批准号:
    10364544
  • 负责人:
  • 金额:
    $ 58.41万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-04-22 至 2022-12-08
  • 项目状态:
    已结题

项目摘要

Project Summary Most bacterial diseases of public health significance are caused by pathogens with an intracellular lifecycle that is integral to their virulence. These microorganisms exploit a variety of host cell functions to ensure their intracellular survival and proliferation, via delivery of effector proteins or toxins that modulate specific host processes, including intracellular membrane transport by vacuolar pathogens. The Golgi apparatus plays a central role in the host secretory traffic of cellular components and is targeted by many bacteria for the purpose of vacuole biogenesis and maintenance or intracellular nutrient acquisition. Little is known, however, about the bacterial effectors that exploit this essential organelle, nor how pathogens subvert its functions for pathogenic purposes. Bacteria of the genus Brucella, which cause the global zoonosis brucellosis, generate a replication-permissive organelle derived from the host endoplasmic reticulum (ER), the Brucella-containing vacuole (rBCV), which is essential to their pathogenesis. rBCV biogenesis requires VirB Type IV secretion system (T4SS)-mediated delivery of effector proteins that modulate specific host secretory functions. We identified several of these effectors, among which BspB targets the conserved oligomeric Golgi (COG) complex, a master regulator of Golgi-associated vesicular trafficking, to promote rBCV biogenesis and bacterial replication. Additional T4SS effectors (BspD and BspF) modulate Golgi- associated trafficking functions, further supporting a previously unsuspected role of the Golgi apparatus in the Brucella intracellular cycle. Our findings also suggest that T4SS effectors (BspB/RicA and BspF/BspD) functionally cooperate in their modulation of membrane transport pathways, arguing that Brucella modulation of Golgi-associated processes results from the integration of multiple effector functions. Here we will test the hypothesis that Brucella delivers an array of T4SS effector proteins that modulate membrane transport functions at the Golgi interface to coordinately promote bacterial proliferation. We will use genetic, cellular and biochemical approaches to first characterize the Golgi transport pathways that contribute to Brucella proliferation and define the targets and functional network of Golgi-targeting T4SS effectors. Second, we will determine the molecular modes of action of the Golgi-targeting T4SS effectors BspB, BspD and BspF. Last, we will define i) how BspB and RicA coordinately modulate ER-Golgi vesicular transport to promote rBCV biogenesis and ii) how BspF and BspD co-modulate TGN-associated transport to promote Brucella replication. The successful completion of this project will uncover bacterial effector- driven mechanisms of modulation of Golgi-associated membrane transport functions and define new paradigms of effector functions and coordination in bacterial pathogens, broadly impacting the research areas of microbial pathogenesis, cell biology and innate immunity.
项目摘要 大多数具有公共卫生意义的细菌性疾病都是由具有细胞内生命周期的病原体引起的 这是他们的毒力不可或缺的一部分。这些微生物利用宿主细胞的各种功能来确保 它们在细胞内的生存和增殖,通过传递调节特定基因的效应蛋白或毒素 寄主过程,包括液泡病原体的细胞膜运输。高尔基仪器 在细胞成分的宿主分泌运输中起核心作用,是许多细菌的靶标 液泡的生物发生和维持或细胞内营养获取的目的。鲜为人知的是, 然而,关于利用这种重要细胞器的细菌效应器,也不是病原体如何颠覆其 具有致病功能。引起全球人畜共患病的布鲁氏菌属细菌 布鲁氏菌病,产生从宿主内质网(ER)衍生的允许复制的细胞器, 含有布鲁氏菌的空泡(RBCV),这在它们的发病机制中是必不可少的。RBCV的生物发生需要 VIRB IV型分泌系统(T4SS)介导的调节特定宿主的效应蛋白的递送 分泌功能。我们确定了这些效应器中的几个,其中BSPB针对保守的 寡聚高尔基体(COG)复合体,高尔基体相关囊泡运输的主要调节者,以促进 RBCV的生物发生和细菌复制。其他T4SS效应器(BspD和BspF)调制高尔基体- 相关的贩运职能,进一步支持高尔基机构在 布鲁氏菌的细胞内循环。我们的发现还表明,T4SS效应器(BSPB/RICA和BSPF/BSPD) 在调节膜转运途径方面进行了功能合作,认为布鲁氏菌 高尔基体相关过程的调制是多个效应器功能整合的结果。这里 我们将检验布鲁氏菌传递一系列T4SS效应蛋白的假设,该蛋白可调节 高尔基体界面的膜转运功能协同促进细菌增殖。我们会 使用遗传、细胞和生化方法首先确定高尔基体运输途径的特征 促进布鲁氏菌增殖并确定高尔基体靶向T4SS的靶点和功能网络 效应器。第二,我们将确定高尔基体靶向T4SS效应器的分子作用模式 BSPB、BSPD和BSPF。最后,我们将定义i)BSPB和RICA是如何协调调制ER-高尔基囊泡的 促进rBCV生物发生的运输和II)BspF和BspD如何共同调节TGN相关的运输 以促进布鲁氏菌的复制。该项目的成功完成将揭示细菌效应器- 高尔基体相关膜转运功能调节的驱动机制和定义新的 细菌病原体中效应器功能和协调的范例,广泛影响这项研究 微生物发病机制、细胞生物学和先天免疫等领域。

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

JEAN A CELLI其他文献

JEAN A CELLI的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('JEAN A CELLI', 18)}}的其他基金

ER-phagy in the functional conversion of the Brucella-containing vacuole
内质网吞噬在含布鲁氏菌液泡功能转换中的作用
  • 批准号:
    10508228
  • 财政年份:
    2022
  • 资助金额:
    $ 58.41万
  • 项目类别:
ER-phagy in the functional conversion of the Brucella-containing vacuole
内质网吞噬在含布鲁氏菌液泡功能转换中的作用
  • 批准号:
    10793320
  • 财政年份:
    2022
  • 资助金额:
    $ 58.41万
  • 项目类别:
Remodeling of intracellular membrane traffic by Brucella effectors
布鲁氏菌效应器对细胞内膜交通的重塑
  • 批准号:
    10764643
  • 财政年份:
    2022
  • 资助金额:
    $ 58.41万
  • 项目类别:
Effectors of Brucella intracellular replication
布鲁氏菌细胞内复制的效应子
  • 批准号:
    9283905
  • 财政年份:
    2017
  • 资助金额:
    $ 58.41万
  • 项目类别:
Effectors of Brucella intracellular replication
布鲁氏菌细胞内复制的效应子
  • 批准号:
    9407764
  • 财政年份:
    2017
  • 资助金额:
    $ 58.41万
  • 项目类别:
Brucella mechanisms of autophagy mediated egress
布鲁氏菌自噬介导的出口机制
  • 批准号:
    8748356
  • 财政年份:
    2014
  • 资助金额:
    $ 58.41万
  • 项目类别:

相似海外基金

SPIDVAC - Improved control of priority animal diseases: Novel vaccines and companion diagnostic tests for African horse sickness, peste des petits ruminants and foot-and-mouth disease
SPIDVAC - 改善重点动物疾病的控制:针对非洲马病、小反刍兽疫和口蹄疫的新型疫苗和伴随诊断测试
  • 批准号:
    10043719
  • 财政年份:
    2022
  • 资助金额:
    $ 58.41万
  • 项目类别:
    EU-Funded
Improved control of priority animal diseases: Novel vaccines and companion diagnostic tests for African horse sickness, peste des petits ruminants and foot- and-mouth disease
改善重点动物疾病的控制:针对非洲马病、小反刍兽疫和口蹄疫的新型疫苗和伴随诊断测试
  • 批准号:
    10059336
  • 财政年份:
    2022
  • 资助金额:
    $ 58.41万
  • 项目类别:
    EU-Funded
Generation of transboundary animal diseases-resistant animals by genetic modification technologies to Rab-GTPases genes
利用Rab-GTP酶基因转基因技术培育跨境动物抗病动物
  • 批准号:
    20K20577
  • 财政年份:
    2020
  • 资助金额:
    $ 58.41万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Pioneering)
Transmission: Astonishing Tales of Human-Animal Diseases
传播:人畜疾病的惊人故事
  • 批准号:
    9096618
  • 财政年份:
    2016
  • 资助金额:
    $ 58.41万
  • 项目类别:
13 Development of magnetometer immunoassay technology for the rapid and cost effective detection of endemic animal diseases and pathogens (zoonoses)
13 开发磁力计免疫测定技术,用于快速且经济有效地检测地方性动物疾病和病原体(人畜共患病)
  • 批准号:
    BB/L011360/1
  • 财政年份:
    2013
  • 资助金额:
    $ 58.41万
  • 项目类别:
    Research Grant
Application of a lipocalin towards a biomarker for livestock animal diseases
脂质运载蛋白在畜牧动物疾病生物标志物中的应用
  • 批准号:
    25660216
  • 财政年份:
    2013
  • 资助金额:
    $ 58.41万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Development of magnetometer immunoassay (MIA) technology for the rapid and cost effective detection of endemic animal diseases and pathogens (zoonoses) in a decentralised, point of use, setting
开发磁力计免疫分析 (MIA) 技术,用于在分散的使用点环境中快速且经济高效地检测地方性动物疾病和病原体(人畜共患病)
  • 批准号:
    101466
  • 财政年份:
    2013
  • 资助金额:
    $ 58.41万
  • 项目类别:
    Collaborative R&D
Establishment of genetic engineering method for Pasteurellaceae bacteria from animal diseases.
动物疫病巴氏杆菌基因工程方法的建立
  • 批准号:
    22580359
  • 财政年份:
    2010
  • 资助金额:
    $ 58.41万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Practical control of pathogens which cases stock animal diseases
畜牧动物疾病病原体的实际控制
  • 批准号:
    21360399
  • 财政年份:
    2009
  • 资助金额:
    $ 58.41万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Environmental evaluation, practical use of the resources and investigation of the domestic animal diseases using the living body information of small antelopes in Africa
利用非洲小羚羊活体信息进行环境评价、资源实用化及家畜疾病调查
  • 批准号:
    21255010
  • 财政年份:
    2009
  • 资助金额:
    $ 58.41万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了