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）进行的细胞-细胞通讯对于多种革兰氏阴性变形菌是常见的，并调节多种生物学功能。QS涉及酰基-HSL生产和随后的细菌群落检测，以监测其细胞密度。酰基-HSL由转录调节子检测，其影响基因表达的全局变化。QS对许多生物体的毒力很重要，包括B类生物病原体鼻疽伯克霍尔德氏菌（鼻疽的病原体）。其中一个B。鼻疽酰基-HSL受体BmaR 5严重损害小鼠和仓鼠的毒力。这些观察结果导致的假设，这种QS受体控制重要的毒力基因的转录调控，抑制BmaRS将阻止这一关键的调节。酰基-HSL受体基因通常与酰基-HSL合酶基因相连，但BmaR 5代表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还不清楚。本申请的目的是通过鉴定其响应的酰基-HSL信号，确定和表征该蛋白质的启动子靶标，以及用高通量生物筛选发现该调节的抑制剂来表征BmaR 5。在追求这些目标的过程中，这种未充分研究的病原体的QS信号网络将开始被阐明，并且将确定对由这种孤儿受体控制的调节子的总体评估，包括潜在的毒力因子。拟议的研究是朝着理解B中QS调节的毒力的长期目标迈出的关键一步。评估QS作为一种新的抗治疗靶点，它将提供有关孤儿QS受体在细菌中的作用的重要信息。B。鼻疽是一种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。这些研究的目的是找到BmaRS控制的毒力因子，并确定BmaR 5抑制剂，可以作为新的治疗选择进行评估。B。鼻疽动物模型是稳健的，并提供了一个极好的系统来评估QS在发病过程中的作用，并首次严格评估抗QS治疗剂在阻断或解决感染中的有效性。B的表征。鼻疽孤儿受体BmaR 5也将有助于目前对孤儿受体在QS中的作用的有限理解。还有B鼻疽是一种新兴的自然病原体B的近亲。这些研究的结果可直接应用于B的QS。假鼻疽

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.