A non-canonical quorum sensing regulator of virulence in Burkholderia pseudomallei

鼻疽伯克霍尔德菌毒力的非规范群体感应调节因子

• 批准号: 8883613
• 负责人: Josephine R Chandler
• 金额: $ 18.05万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8883613
• 关键词: Address; Alleles; Animal Model; Animals; Autistic Disorder; Behavior; Biological Models; Biological Neural Networks; Caenorhabditis elegans; Calcium; Calcium Channel; Calcium Signaling; Candidate Disease Gene; Cells; Collaborations; Confocal Microscopy; Core Facility; Data; Defect; Development; Diagnosis; Disease; Disease Pathway; Embryonic Development; Epilepsy; Evoked Potentials; Excision; Exocytosis; Gene Expression Profile; Genes; Genetic; Genetic Models; Genetic Transcription; Goals; Growth; Homologous Gene; Human; Immobilization; Ion Channel; Lead; Link; Literature; Maintenance; Mediating; Mental Retardation; Messenger RNA; Microfabrication; Microfluidics; Microscopy; Molecular; Molecular Analysis; Mood Disorders; Morphology; Mutation; Nervous system structure; Neuromuscular Junction; Neurons; Pathway interactions; Property; Proteins; RNA Interference; RNA Sequences; Role; Signal Transduction; Structure; Synapses; System; Technology; Testing; Time; Translations; Vesicle; Work; base; calcium indicator; calmyrin; experience; functional status; gain of function; gene function; human disease; in vivo; in vivo Model; insight; loss of function; loss of function mutation; mutant; neuromuscular system; neuron development; neurotransmission; next generation; painful neuropathy; response; small molecule; synaptic function; synaptogenesis; transcriptome sequencing; voltage

Burkholderia pseudomallei causes melioidosis infections and is currently the third leading cause of death in Northeast Thailand. Melioidosis is particularly difficult to treat due to intrinsic resistance to antibiotics. Despite the prevalence of melioidosis there is currently a limited understanding of B. pseudomallei pathogenesis. This research program is focused on a virulence regulator in B. pseudomallei, BpsR4. BpsR4 is a member of the LuxR family of transcriptional regulators that are involved in a type of bacterial communication called quorum sensing. Typically LuxR proteins induce target gene expression in response to acyl-homoserine lactone (AHL) quorum-sensing signals. However, BpsR4 induces transcription of virulence genes in a manner that is AHL-independent. Interestingly, BpsR4 is activated by antibiotics (trimeothoprim and piperacillin) that regulate BpsR4 at the transcriptional level. To our knowledge BpsR4 is the first conserved LuxR-family protein that is AHL-independent, and the role of antibiotics in activating BpsR4 or other LuxR-family proteins is totally unknown. Although BpsR4 is important for virulence in a C. elegans model host, it is also unknown if BpsR4 induces virulence gene transcription during host infections. Our long-term goal is to understand how LuxR-family proteins promote bacterial survival in different environments, including the host. The objective of this application is to determine how antibiotics induce BpsR4 transcription and the importance of BpsR4 in regulating virulence gene expression in the host. Our central hypothesis is that antibiotics activate BpsR4 through unknown antibiotic-responsive transcriptional regulator(s) and that BpsR4 induces virulence gene expression during C. elegans infection. This proposal aims to i) identify antibiotic-responsive BpsR4 regulators and ii) evaluate BpsR4 induction of virulence genes during host infections. Because BpsR4 is a new class of LuxR-family proteins the studies proposed are expected to expand the current view of the LuxR family. The proposed experiments will also provide us with experimental data critical for building a picture of how antibiotics regulate BpsR4 expression and how BpsR4 promotes virulence during infection. This is significant because the results are expected to increase the currently limited understanding of how B. pseudomallei causes disease, and may ultimately lead to new strategies to control and treat melioidosis.

类鼻疽伯克霍尔德菌引起类鼻疽感染，目前是泰国东北部第三大死亡原因。由于对抗生素的内在耐药性，类鼻疽特别难以治疗。尽管类鼻疽的流行，但目前对B的了解有限。假性鼻疽发病机制这项研究计划的重点是在B的毒力调节。假鼻疽、BpsR4. BpsR4是转录调节因子LuxR家族的一员，参与一种称为群体感应的细菌通讯。典型地，LuxR蛋白响应于酰基高丝氨酸内酯（阿勒）群体感应信号诱导靶基因表达。然而，BpsR4诱导转录的毒力基因的方式是AHL独立的。有趣的是，BpsR4被在转录水平上调节BpsR4的抗生素（trimeothoprim和哌拉西林）激活。据我们所知，BpsR4是第一个不依赖AHL的保守LuxR家族蛋白，抗生素在激活BpsR4或其他LuxR家族蛋白中的作用是完全未知的。虽然BpsR4对C.虽然BpsR4是线虫模式宿主，但BpsR4是否在宿主感染期间诱导毒力基因转录也是未知的。我们的长期目标是了解LuxR家族蛋白如何促进细菌在不同环境中的存活，包括宿主。本申请的目的是确定抗生素如何诱导BpsR4转录以及BpsR4在调节宿主毒力基因表达中的重要性。我们的中心假设是，抗生素通过未知的免疫应答转录调节因子激活BpsR4，并且BpsR4在C.线虫感染该提案旨在i）鉴定抗宿主应答性BpsR4调节剂和ii）评估宿主感染期间BpsR4对毒力基因的诱导。由于BpsR4是一类新的LuxR家族蛋白，因此所提出的研究有望扩展LuxR家族的现有观点。拟议的实验还将为我们提供实验数据，这些数据对于构建抗生素如何调节BpsR4表达以及BpsR4如何在感染过程中促进毒力至关重要。这是重要的，因为这些结果有望增加目前有限的理解如何B。假鼻疽引起疾病，并可能最终导致新的战略，以控制和治疗类鼻疽。