Global regulatory interactions in bacterial pathogenesis

细菌发病机制中的全局调控相互作用

• 批准号: 6802916
• 负责人: Brian Akerley
• 金额: $ 38.8万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6802916
• 关键词: Haemophilus influenzae; bacteria infection mechanism; bacterial genetics; biological signal transduction; disease /disorder model; gene mutation; genetic regulation; laboratory rat; lipopolysaccharides; microarray technology; oxidation reduction reaction; polymerase chain reaction; respiratory epithelium; respiratory infections; virulence

DESCRIPTION (provided by applicant): Haemophilus influenzae efficiently and chronically colonizes the human nasopharyngeal mucosa, and is capable of causing invasive disease including otitis media, pneumonia, and, more rarely, meningitis. A number of factors involved in H. influenzae virulence have been identified in the pre-genomic era. Taking advantage of the genome sequence and the advent of new technologies, such as global expression profiling, we intend to advance understanding of critical virulence characteristics of this organism. Lipopolysaccharide (LPS) structural modifications are essential virulence determinants for H. influenzae. Using expression profiling with DNA microarrays, complemented by classical approaches, we have recently uncovered a previously unappreciated link between redox regulation and LPS modifications in H. influenzae. In addition, we have isolated a mariner transposon insertion mutation in H. influenzae that disrupts redox control over one such modification (addition of a phosphorylcholine epitope, termed ChoP, to the LPS) and also results in a pronounced colonization defect in an animal model of H. influenzae infection. These observations are of potential significance for in vivo modulation of the LPS structure by environmental signals. We propose to use such signaling and regulatory mutants generated in our laboratory to examine the role of redox signaling in controlling virulence genes in H. influenzae. Global genomic approaches we have developed for studies of H. influenzae will facilitate our analysis of how LPS modifications are modulated in response to environmental conditions. We will also determine whether other genes that play a role in pathogenesis are coregulated, inversely regulated, or constitutively transcribed under the varied redox conditions that affect LPS modification. We believe that these studies will provide important insights into the relationship between physiological adaptations to the host environment and the coordinated production of bacterial cell-surface structures critical for interactions with host cells or for evading the immune response. Specifically, we will: 1. Characterize the redox control mechanisms involved in the regulation of the ChoP cell surface LPS modification. 2. Investigate the role of signaling pathways in H. influenzae in the context of epithelial cell interactions and in a model of respiratory tract infection. 3. Examine coordinate regulation of virulence factors by redox signaling systems.

描述（由申请人提供）：嗜血杆菌有效地并长期地殖民人类鼻咽粘膜，并能够引起侵袭性疾病，包括耳炎培养基，肺炎，以及更罕见的脑膜炎。在基因组前时代已经确定了流感毒素毒力的许多因素。利用基因组序列和新技术的出现，例如全球表达谱分析，我们打算促进对这种生物的关键毒力特征的理解。脂多糖（LPS）结构修饰是流感h。使用与经典方法相辅相成的DNA微阵列的表达谱分析，我们最近发现了氧化还原调控与流感h.; th.H.此外，我们已经在流感流感的h. h. s. h. s. h. s. h. s. h. sposon中分离了水手转座子插入突变，该突变破坏了对一种改性的氧化还原控制（添加了磷酸胆碱表位，称为CHOP，在LPS中），也导致了h。H.h. th. rancezae感染的动物模型中明显的定植。这些观察结果对于通过环境信号对LPS结构的体内调节具有潜在的意义。我们建议使用我们实验室中产生的这种信号传导和调节突变体，以检查氧化还原信号在控制毒力性基因中的作用。我们开发的全球基因组方法用于研究H.流感的研究，将有助于我们分析如何根据环境条件调节LPS修饰。我们还将确定在发病机理中发挥作用的其他基因是否在影响LPS修饰的各种氧化还原条件下进行核心，成反比或组成式转录。我们认为，这些研究将为对宿主环境的生理适应与宿主细胞表面结构的协调生产之间的关系提供重要的见解，这对于与宿主细胞相互作用或逃避免疫反应至关重要。具体而言，我们将：1。表征与Chop Cell表面LPS修饰的调节有关的氧化还原控制机制。 2。在上皮细胞相互作用和呼吸道感染模型中，研究信号通路在流感烟草中的作用。 3。检查氧化还原信号系统对毒力因子的坐标调节。