Bartonella: dissecting niche-specific adaptation in a human pathogen

巴尔通体:剖析人类病原体的生态位特异性适应

基本信息

  • 批准号:
    9087141
  • 负责人:
  • 金额:
    $ 47.26万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-07-01 至 2018-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Bartonella quintana (BQ) is a gram-negative human pathogen that causes serious and potentially fatal infections, and is the leading cause of culture-negative heart valve infection in the US. BQ also causes persistent bacteremia and fatal illness in immunocompromised individuals with cancer and HIV/AIDS. BQ is transmitted to humans by the body louse; humans become infected when the BQ bacteria in the louse feces are introduced into the louse bite wound by scratching. BQ alternates between two very different niches: the bloodstream of the homeothermic mammalian reservoir (37�C) and the gut of the poikilothermic arthropod vector (28�C). Virtually nothing is known about the virulence factors involved in the transition between the host and arthropod vector. However, the arthropod niche is an essential part of the life cycle of BQ, and it is required for infection of humans. To surviv and proliferate, BQ bacteria must adapt rapidly during the shift between these two disparate environments. Such adaptation to environmental changes and stresses are frequently mediated by alternative sigma factor subunits of the RNA polymerase. We found that rpoE, an uncharacterized sigma factor gene homologous to the extracytoplasmic function (ECF) sigma factor of several alpha-proteobacteria, is significantly up-regulated at the 28�C temperature of the arthropod vector. In addition, rpoE is necessary for colonization of lice by BQ. Thus, BQ appears to have uniquely co-opted the alpha-proteobacterial general stress response system to up-regulate genes at 28�C to adapt to its vector. Our long-term goal is to delineate the transcriptional program employed by the BQ pathogen to permit survival in the transition to, and within the arthropod niche, with the goal of identifying common regulatory themes and targets with potential applicability to other arthropod-borne bacterial pathogens. The short-term goal, and the focus of this proposal, is to identify the niche-specific genes involved in the transition between the arthropod and human host, and the regulatory network controlling their expression in BQ. The specific aims of this proposal are: 1) to determine the in vivo role of RpoE-directed transcription in colonization of the human body louse by BQ; and 2) to define the BQ RpoE regulon response to louse stressors in vitro, and identify RpoE-responsive promoter elements involved in the BQ human-louse transition. Successful completion of these specific aims will have a positive impact by: 1) identifying factors and regulatory networks that are necessary for pathogen transition between niches; 2) leveraging this knowledge to identify targets for preventive and therapeutic intervention in arthropod-borne pathogens; and 3) elucidating the unexplored and novel utilization of the alpha-proteobacterial ECF15 class of s factors for adaptation by the BQ human pathogen. Collectively, our preliminary data and the research proposed herein represent a new paradigm in sigma factor adaptive response for both the ECF15 s factor field, and the bacterial pathogenesis field.
描述(由申请人提供):金塔纳巴尔通体(BQ)是一种革兰氏阴性的人类病原体,可引起严重和潜在致命的感染,是美国培养阴性心脏瓣膜感染的主要原因。BQ还会在患有癌症和艾滋病毒/艾滋病的免疫功能低下的个体中引起持续性菌血症和致命疾病。BQ通过体虱传播给人类;当虱子粪便中的BQ细菌通过抓挠进入虱子咬伤的伤口时,人类就会被感染。BQ在两个非常不同的生态位之间交替:恒温哺乳动物宿主(37℃)的血液和变温节肢动物载体(28℃)的肠道。在宿主和节肢动物媒介之间的转化过程中涉及的毒力因素几乎一无所知。然而,节肢动物生态位是BQ生命周期的重要组成部分,也是人类感染所必需的。为了生存和繁殖,BQ细菌必须在这两种完全不同的环境之间快速适应。这种对环境变化和压力的适应通常是由RNA聚合酶的备选sigma因子亚基介导的。我们发现,在节肢动物载体的28℃温度下,与几种α -变形细菌的胞质外功能(ECF) sigma因子同源的未被鉴定的sigma因子基因rpoE显著上调。此外,rpoE是BQ定殖虱的必要条件。因此,BQ似乎独特地选择了α -变形菌一般应激反应系统,在28℃下上调基因以适应其载体。我们的长期目标是描述BQ病原体所采用的转录程序,以允许其在节肢动物生态位的过渡中生存,并在节肢动物生态位内生存,目标是确定共同的调控主题和潜在的适用于其他节肢动物传播的细菌病原体的靶点。短期目标,也是本研究的重点,是确定参与节肢动物与人类宿主之间转变的生态位特异性基因,以及在BQ中控制其表达的调控网络。本提案的具体目的是:1)确定rpoe定向转录在BQ定植人体虱子中的体内作用;2)在体外确定BQ RpoE调控对虱子应激源的响应,并鉴定参与BQ人-虱子转化的RpoE响应启动子元件。成功完成这些具体目标将产生积极影响:1)确定病原体在生态位之间转换所必需的因素和调控网络;2)利用这些知识来确定节肢动物传播病原体的预防和治疗干预目标;3)阐明了α -蛋白细菌ECF15类5个因子在BQ人类病原体适应中的未开发和新利用。总的来说,我们的初步数据和本文提出的研究代表了ecf15s因子领域和细菌发病领域的sigma因子适应性反应的新范式。

项目成果

期刊论文数量(1)
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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JANE E KOEHLER其他文献

JANE E KOEHLER的其他文献

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{{ truncateString('JANE E KOEHLER', 18)}}的其他基金

Bartonella: dissecting niche-specific adaptation in a human pathogen
巴尔通体:剖析人类病原体的生态位特异性适应
  • 批准号:
    8691724
  • 财政年份:
    2013
  • 资助金额:
    $ 47.26万
  • 项目类别:
Bartonella: dissecting niche-specific adaptation in a human pathogen
巴尔通体:剖析人类病原体的生态位特异性适应
  • 批准号:
    8579795
  • 财政年份:
    2013
  • 资助金额:
    $ 47.26万
  • 项目类别:
BARTONELLA MODEL FOR AN AIDS OPPORTUNISTIC PATHOGEN
艾滋病机会性病原体的巴尔通体模型
  • 批准号:
    7959000
  • 财政年份:
    2009
  • 资助金额:
    $ 47.26万
  • 项目类别:
BARTONELLA MODEL FOR AN AIDS OPPORTUNISTIC PATHOGEN
艾滋病机会性病原体的巴尔通体模型
  • 批准号:
    7715578
  • 财政年份:
    2008
  • 资助金额:
    $ 47.26万
  • 项目类别:
BARTONELLA MODEL FOR AN AIDS OPPORTUNISTIC PATHOGEN
艾滋病机会性病原体的巴尔通体模型
  • 批准号:
    7562167
  • 财政年份:
    2007
  • 资助金额:
    $ 47.26万
  • 项目类别:
BARTONELLA MODEL FOR AN AIDS OPPORTUNISTIC PATHOGEN
艾滋病机会性病原体的巴尔通体模型
  • 批准号:
    7349656
  • 财政年份:
    2006
  • 资助金额:
    $ 47.26万
  • 项目类别:
BARTONELLA MODEL FOR AN AIDS OPPORTUNISTIC PATHOGEN
艾滋病机会性病原体的巴尔通体模型
  • 批准号:
    7165459
  • 财政年份:
    2005
  • 资助金额:
    $ 47.26万
  • 项目类别:
BARTONELLA MODEL FOR AN AIDS OPPORTUNISTIC PATHOGEN
艾滋病机会性病原体的巴尔通体模型
  • 批准号:
    6971454
  • 财政年份:
    2004
  • 资助金额:
    $ 47.26万
  • 项目类别:
BARTONELLA MODEL FOR AN AIDS OPPORTUNISTIC PATHOGEN
艾滋病机会性病原体的巴尔通体模型
  • 批准号:
    6940416
  • 财政年份:
    2003
  • 资助金额:
    $ 47.26万
  • 项目类别:
Mechanisms of Bartonella Virulence in AIDS Patients
艾滋病患者巴尔通体的毒力机制
  • 批准号:
    7554614
  • 财政年份:
    2002
  • 资助金额:
    $ 47.26万
  • 项目类别:

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致病性α变形菌保守毒力相关遗传途径的功能和调控特征
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