Quorum Sensing in Burkholderia mallei

鼻疽伯克霍尔德菌中的群体感应

• 批准号: 7770852
• 负责人: Josephine R Chandler
• 金额: $ 5.22万
• 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 2011-04-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7770852
• 关键词: Affect; Animal Model; Bacteria; Biological; Biological Process; Burkholderia mallei; Burkholderia pseudomallei; Categories; Cell Communication; Cell Density; Cells; Communities; Detection; 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 - 耶洛舍碱内酯（酰基-HSL）群体传感（QS）通过各种革兰氏阴性蛋白细菌常见，并调节各种生物学功能。 QS涉及细菌群落的酰基-HSL产生以及随后的检测，以监测其细胞密度。通过转录调节剂检测到酰基-HSL，这会影响基因表达的全局变化。 QS对于许多生物体的毒力很重要，包括BioAgent Burkholderia Mallei（腺体的致病药物）。 B. mallei酰基-HSL受体之一BMAR5的破坏严重损害了小鼠和仓鼠的毒力。这些观察结果导致了以下假设：该QS受体控制重要的毒力基因的转录调控，而BMAR的抑制作用将阻止这种关键调节。酰基-HSL受体基因通常与酰基-HSL合酶基因有关，但是BMAR5代表一个称为孤儿的受体亚组，因为没有链接的酰基-HSL合酶基因。孤儿受体的生物学意义尚不清楚。该应用的目的是通过识别其响应的酰基-HSL信号来表征BMAR5，确定和表征该蛋白质的启动子靶标，并通过高吞吐量生物筛选来找到该调节的抑制剂。在追求这些目标时，将开始阐明这种研究的病原体的QS信号网络，并将确定对该孤儿受体控制的调节子的全球评估，包括潜在的毒力因子。拟议的研究是朝着长期目标迈出的至关重要的一步，即了解QS调节的毒力，并将QS评估为一种新型的抗治疗靶标，它将提供有关孤儿受体在细菌中的作用的重要信息。 B. Mallei是B类Biothreat剂，其特征性毒力因子和有限的治疗选择。这些研究旨在找到BMAR控制的毒力因子，并鉴定可以评估为新型治疗选择的BMAR5抑制剂。 B. mallei动物模型是强大的，并提供了一个出色的系统来评估QS在发病机理中的作用，并首次批判性地评估抗QS疗法在阻断或解决感染中的有效性。 Mallei孤儿受体BMAR5的表征也将有​​助于当前对孤儿受体在QS中的作用的了解。麦芽芽孢杆菌也是新出现的天然病原体假单胞菌的非常亲密的亲戚，这些研究的结果可能直接适用于假单胞菌芽孢杆菌中的QS。