Quorum Sensing in Burkholderia mallei

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）进行细胞间通信是多种革兰氏阴性变形杆菌常见的，并调节多种生物学功能。QS涉及酰基- hsl的生产和随后的细菌群落检测，以监测其细胞密度。acyl - hsl通过转录调控因子检测，影响基因表达的全局变化。QS对许多生物的毒力都很重要，包括B类生物制剂马氏伯克氏菌，它是腺病的病原体。破坏一种麦氏杆菌酰基- hsl受体BmaR5，严重损害小鼠和仓鼠的毒力。这些观察结果导致了一个假设，即这个QS受体控制着重要毒力基因的转录调控，而抑制BmaRS将阻断这一关键调控。酰基- hsl受体基因通常与酰基- hsl合成酶基因相连，但由于没有酰基- hsl合成酶基因，BmaR5代表了被称为孤儿的受体亚群。孤儿受体的生物学意义尚不清楚。本应用程序的目的是通过识别其响应的酰基- hsl信号来表征BmaR5，确定和表征该蛋白的启动子靶点，并通过高通量生物筛选找到该调节的抑制剂。为了实现这些目标，将开始阐明这种未被充分研究的病原体的QS信号网络，并确定由这种孤儿受体控制的调控的全球评估，包括潜在的毒力因子。该研究是了解麦氏芽孢杆菌中QS调控的毒力和评估QS作为新的抗治疗靶点的长期目标的关键一步，它将为孤儿QS受体在细菌中的作用提供重要信息。麻孢杆菌是一种B类生物威胁剂，具有很少的特征性毒力因子和有限的治疗选择。这些研究旨在发现BmaR5控制的毒力因子，并确定BmaR5抑制剂，这些抑制剂可以作为新的治疗选择进行评估。B. mallei动物模型是稳健的，并提供了一个很好的系统来评估QS在发病机制中的作用，并首次批判性地评估抗QS治疗在阻断或解决感染方面的有效性。对马来芽孢杆菌孤儿受体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，麦氏双歧杆菌与一种新兴的天然病原菌假麦氏双歧杆菌有很近的亲缘关系，这些研究结果可能直接适用于假麦氏双歧杆菌的QS。

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.