Quorum Sensing in Burkholderia mallei

鼻疽伯克霍尔德菌中的群体感应

• 批准号: 7482708
• 负责人: Josephine R Chandler
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-16 至 2011-03-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7482708
• 关键词: Affect; Animal Model; Bacteria; Biological; Biological Process; Burkholderia mallei; Burkholderia pseudomallei; Categories; Cell Communication; Cell Density; Cells; Communities; Detection; Disruption; Effectiveness; Gene Expression; Genes; Glanders; Global Change; Hamsters; Infection; Lead; Link; Monitor; Mus; Organism; Orphan; Pathogenesis; Production; Proteins; Proteobacteria; Receptor Gene; Regulation; Regulon; Relative (related person); Research; Role; Signal Transduction; Subgroup; System; Therapeutic; Time; Transcriptional Regulation; Virulence; Virulence Factors; biothreat; homoserine lactone; inhibitor/antagonist; novel; pathogen; promoter; quorum sensing; receptor; therapeutic target

DESCRIPTION (provided by applicant): Cell-cell communication by acyl-homoserine lactone (acyl-HSL) quorum sensing (QS) is common to a variety of Gram-negative Proteobacteria and regulates diverse biological functions. QS involves acyl-HSL production and subsequent detection by a community of bacteria in order to monitor their cell density. Acyl-HSLs are detected by transcriptional regulators, which affect global changes in gene expression. QS is important for virulence in many organisms, including the category B bioagent Burkholderia mallei, the causative agent of glanders. Disruption of one of the B. mallei acyl-HSL receptors, BmaR5, severely impairs virulence in mice and hamsters. These observations lead to the hypothesis that this QS receptor controls transcriptional regulation of important virulence genes, and that inhibition of BmaRS will block this crucial regulation. Acyl-HSL receptor genes are commonly linked to acyl-HSL synthase genes, but BmaR5 represents a subgroup of receptors called orphans because there is no linked acyl-HSL synthase gene. The biological significance of orphan receptors is not well understood. The aims of this application are to characterize BmaR5 by identifying the acyl-HSL signal to which it responds, determining and characterizing promoter targets of this protein, and finding inhibitors of this regulation with a high- throughput biological screen. In pursuing these aims, the QS signaling networks of this understudied pathogen will begin to be elucidated and a global assessment of the regulon controlled by this orphan receptor, including potential virulence factors, will be determined. The proposed research is a crucial step towards the long-term objective of understanding QS-regulated virulence in B. mallei and assessing QS as a novel anti-therapeutic target and it will provide important information about the role of orphan QS receptors in bacteria. B. mallei is a category B biothreat agent with few characterized virulence factors and limited treatment options. These studies aim to find BmaRS-controlled virulence factors and identify BmaR5 inhibitors that can be evaluated as novel treatment options. B. mallei animal models are robust and provide an excellent system to assess the role of QS during pathogenesis and for the first time critically evaluate the effectiveness of anti-QS therapeutics in blocking or resolving infections. Characterization of the B. mallei orphan receptor BmaR5 will also contribute to the currently limited understanding of the role of orphan receptors in QS. Also B. mallei are a very close relative of an emerging natural pathogen, B. pseudomallei, and the results of these studies may be directly applicable to QS in B. pseudomallei.

描述（由申请人提供）：通过酰基高丝氨酸内酯（酰基-HSL）群体感应（QS）进行的细胞间通讯对于多种革兰氏阴性变形菌来说是常见的，并调节多种生物功能。 QS 涉及酰基-HSL 的产生以及随后由细菌群落进行的检测，以监测其细胞密度。 Acyl-HSL 由转录调节因子检测，影响基因表达的整体变化。 QS 对于许多生物体的毒力很重要，包括 B 类生物制剂鼻疽伯克霍尔德氏菌（鼻疽病的病原体）。鼻疽杆菌酰基 HSL 受体之一 BmaR5 的破坏会严重损害小鼠和仓鼠的毒力。这些观察结果得出这样的假设：该 QS 受体控制重要毒力基因的转录调节，而抑制 BmaRS 将阻断这一关键调节。酰基-HSL 受体基因通常与酰基-HSL 合酶基因连接，但 BmaR5 代表了称为孤儿的受体亚组，因为没有连接的酰基-HSL 合酶基因。孤儿受体的生物学意义尚不清楚。本应用的目的是通过鉴定 BmaR5 响应的酰基-HSL 信号、确定和表征该蛋白的启动子靶标以及通过高通量生物筛选寻找该调节的抑制剂来表征 BmaR5。为了实现这些目标，我们将开始阐明这种尚未充分研究的病原体的 QS 信号网络，并对这种孤儿受体控制的调节子（包括潜在的毒力因子）进行全面评估。拟议的研究是实现了解鼻疽中 QS 调节毒力和评估 QS 作为新型抗治疗靶点的长期目标的关键一步，它将提供有关细菌中孤儿 QS 受体作用的重要信息。鼻疽杆菌是一种 B 类生物威胁因子，特征毒力因子很少，治疗选择也有限。这些研究旨在寻找 BmaRS 控制的毒力因子并确定可作为新型治疗选择进行评估的 BmaR5 抑制剂。鼻疽动物模型非常强大，为评估 QS 在发病机制中的作用提供了一个出色的系统，并首次严格评估抗 QS 疗法在阻止或解决感染方面的有效性。 B. mallei 孤儿受体 BmaR5 的表征也将有​​助于目前对孤儿受体在 QS 中的作用的有限理解。此外，鼻疽伯克氏菌是一种新出现的天然病原体拟鼻疽伯克氏菌的近亲，这些研究的结果可能直接适用于类鼻疽伯克氏菌的 QS。