Quorum Sensing in Burkholderia mallei

描述(由申请人提供)：通过酰基高丝氨酸内酯(acyl-HSL)进行细胞间通讯(acyl-HSL)群体感应(QS)是各种革兰氏阴性变形杆菌共有的，并调节不同的生物学功能。QS涉及酰基-HSL的产生和随后细菌群落的检测，以监测它们的细胞密度。酰基-HSL是由转录调节因子检测的，它影响基因表达的全球变化。QS对许多生物体的毒力都很重要，包括B类生物制剂马来伯克霍尔德氏菌，它是扁虱的病原体。破坏马来杆菌酰基-HSL受体之一BmaR5会严重损害小鼠和仓鼠的毒力。这些观察结果导致了一种假设，即这种QS受体控制着重要毒力基因的转录调控，而抑制BmaRs将阻止这一关键调控。酰基-HSL受体基因通常与酰基-HSL合成酶基因连锁，但BmaR5代表称为孤儿的受体亚群，因为没有连锁的酰基-HSL合成酶基因。孤儿受体的生物学意义还没有被很好地理解。本申请的目的是通过鉴定BmaR5反应的酰基-HSL信号，确定和表征该蛋白的启动子靶标，并用高通量生物筛选寻找该调控的抑制剂，从而表征BmaR5。在追求这些目标的过程中，将开始阐明这种未被研究的病原体的QS信号网络，并将确定对这种孤儿受体控制的调节子的全球评估，包括潜在的毒力因子。这项拟议的研究是朝着理解QS调节的马来芽胞杆菌毒力并评估QS作为新的抗治疗靶点的长期目标迈出的关键一步，它将提供关于孤儿QS受体在细菌中的作用的重要信息。马来芽胞杆菌是一种B类生物制剂，几乎没有典型的毒力因子，治疗选择也有限。这些研究旨在寻找BmaRS控制的毒力因子，并确定可作为新的治疗选择进行评估的BmaR5抑制剂。B.Mallei的动物模型是可靠的，并提供了一个很好的系统来评估QS在发病过程中的作用，并首次关键地评估了抗QS疗法在阻断或解决感染方面的有效性。对B.Mallei孤儿受体BmaR5的表征也将有助于目前对孤儿受体在QS中作用的有限了解。此外，马来假单胞菌与一种新出现的自然病原菌假单胞菌有非常近的亲缘关系，这些研究结果可能直接适用于假单胞菌的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.