Regulation of the virulence factor PlcH in Pseudomonas aeruginosa

铜绿假单胞菌毒力因子PlcH的调控

基本信息

项目摘要

Pseudomonas aeruginosa (Pa) is an important opportunistic human pathogen that deploys a variety of virulence factors, each playing roles in different infection sites or with different cell types. One important virulence factor of Pa is the hemolytic phospholipase C/sphingomyelinase, PlcH. plcH mutants are defective in a wide range of infection models and PlcH expression by strains has been correlated to human disease severity and differential treatment efficacy. There are three currently known inputs to PlcH expression: induction by phosphate starvation, induction by glycine betaine, and repression by low oxygen environments. While each of these regulatory paths have been described, there remain important gaps in our understanding of PlcH regulation as well as alterations in these regulatory pathways in specific disease contexts. In this proposal, we will determine the identity and mechanisms of previously unidentified transcriptional and posttranslational regulation of PlcH and determine the role of altered PlcH regulation during Pa adaptation in the lungs of people with cystic fibrosis. Despite the contribution of PlcH to Pa virulence, study of its regulation lags behind that of other virulence factors. Here we present preliminary data for novel transcriptional regulation of plcH, identification of a new post- translational PlcH regulatory step, and present changes to metabolic pathways directly upstream of plcH induction that occur within the cystic fibrosis lung. Our hypothesis is that PlcH production and export is regulated at multiple levels and that these regulatory steps work to titrate the flux of enzymatic products and to avoid damage to producing cells. We have longstanding experience with PlcH and a large experimental toolkit with which to approach its regulation. We are well positioned to understand the mechanisms behind uncharacterized PlcH regulatory pathways and to identify new regulatory inputs. We will address PlcH regulation by (i) determining the mechanisms of uncharacterized plcH transcriptional regulation and the importance of each mechanism of transcriptional induction, (ii) deciphering post-translational control mechanisms for PlcH, and (iii) examining alteration in PlcH expression by pathoadaptive mutations occurring during long term cystic fibrosis lung infections. The work proposed here will allow us to have a more complete understanding of PlcH regulation, providing biological insight and exposing potential targets for inhibition of PlcH production.
摘要铜绿假单胞菌是一种重要的机会致病菌,具有多种毒力。 因子,每个因子在不同的感染部位或不同的细胞类型中发挥作用。一个重要的毒力因素 Pa是溶血性磷脂酶C/鞘磷脂酶,PlcH。PLCCH突变体在广泛的 感染模式和菌株的PlcH表达与人类疾病的严重程度和分化程度相关 治疗效果。目前已知PlcH的表达有三个输入:由磷酸盐饥饿诱导, 甘氨酸甜菜碱诱导,低氧环境抑制。虽然这些监管路径中的每一条 ,在我们对PlcH调节以及改变的理解上仍然存在着重要的差距 在特定疾病背景下的这些调控途径中。在这项提案中,我们将确定身份和 先前未知的plcH转录和翻译后调节机制并确定 囊性纤维化症患者肺PA适应过程中PlcH调节改变的作用。 尽管PlcH对PA的毒力有贡献,但对其调控的研究落后于其他毒力因子。 在这里,我们提供了新的plcH转录调控的初步数据,鉴定了一个新的POST-1。 翻译plcH调控步骤,并呈现plcH上游直接代谢途径的变化 发生在囊性纤维化肺内的诱导。我们的假设是plch的生产和出口是受监管的 这些监管步骤的作用是滴定酶产品的流量,并避免 对生产细胞的损害。我们对PlcH有长期的经验,并有一个大型实验工具包 用什么来接近它的监管。我们已经做好了充分的准备来理解非特色化背后的机制 PlcH调控途径,并确定新的调控输入。我们将通过(I)解决PlcH监管问题 确定未知的plcH转录调控机制及其各自的重要性 转录诱导机制,(Ii)破译plcH的翻译后控制机制,以及(Iii) 通过发生在长期囊性纤维化过程中的病理适应性突变检测PlcH表达的变化 肺部感染。 这里提出的工作将使我们对Plch的监管有一个更完整的了解,提供 生物学洞察力和暴露潜在的靶点,以抑制PlcH的产生。

项目成果

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MATTHEW J WARGO其他文献

MATTHEW J WARGO的其他文献

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{{ truncateString('MATTHEW J WARGO', 18)}}的其他基金

Pseudomonas detection and metabolism of sphingosine
假单胞菌检测和鞘氨醇代谢
  • 批准号:
    8581641
  • 财政年份:
    2012
  • 资助金额:
    $ 37.88万
  • 项目类别:
Pseudomonas detection and metabolism of sphingosine
假单胞菌检测和鞘氨醇代谢
  • 批准号:
    8760307
  • 财政年份:
    2012
  • 资助金额:
    $ 37.88万
  • 项目类别:
Pseudomonas detection and metabolism of sphingosine
假单胞菌检测和鞘氨醇代谢
  • 批准号:
    9170956
  • 财政年份:
    2012
  • 资助金额:
    $ 37.88万
  • 项目类别:
Pseudomonas detection and metabolism of sphingosine
假单胞菌检测和鞘氨醇代谢
  • 批准号:
    8417470
  • 财政年份:
    2012
  • 资助金额:
    $ 37.88万
  • 项目类别:
VERMONT COBRE PROJECT 7: BETAINE REGULATION OF PSEUDOMONAS VIRULENCE
佛蒙特州 COBRE 项目 7:甜菜碱对假单胞菌毒力的调节
  • 批准号:
    8360778
  • 财政年份:
    2011
  • 资助金额:
    $ 37.88万
  • 项目类别:
CHARACTERIZATION OF PSEUDOMONAS PHOSPHOLIPASES INVOLVED IN VIRULENCE
参与毒力的假单胞菌磷脂酶的表征
  • 批准号:
    8168184
  • 财政年份:
    2010
  • 资助金额:
    $ 37.88万
  • 项目类别:
VERMONT COBRE PROJECT 7: BETAINE REGULATION OF PSEUDOMONAS VIRULENCE
佛蒙特州 COBRE 项目 7:甜菜碱对假单胞菌毒力的调节
  • 批准号:
    8167737
  • 财政年份:
    2010
  • 资助金额:
    $ 37.88万
  • 项目类别:

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