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: 6894832
• 负责人: Brian Akerley
• 金额: $ 38.71万
• 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/6894832
• 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）：流感嗜血杆菌能够有效且长期地定植于人类鼻咽粘膜，并且能够引起侵袭性疾病，包括中耳炎、肺炎，以及更罕见的脑膜炎。在前基因组时代已经确定了与流感嗜血杆菌毒力有关的许多因素。利用基因组序列和全局表达谱等新技术的出现，我们打算加深对该生物体关键毒力特征的了解。脂多糖（LPS）结构修饰是流感嗜血杆菌的重要毒力决定因素。通过使用 DNA 微阵列表达谱分析并辅以经典方法，我们最近发现了流感嗜血杆菌中氧化还原调节与 LPS 修饰之间先前未被认识到的联系。此外，我们在流感嗜血杆菌中分离出了一种水手转座子插入突变，该突变破坏了对此类修饰（在 LPS 中添加称为 ChoP 的磷酸胆碱表位）的氧化还原控制，并且还导致流感嗜血杆菌感染的动物模型中出现明显的定植缺陷。这些观察对于环境信号对 LPS 结构的体内调节具有潜在意义。我们建议使用我们实验室产生的此类信号传导和调节突变体来检查氧化还原信号传导在控制流感嗜血杆菌毒力基因中的作用。我们为流感嗜血杆菌研究开发的全球基因组方法将有助于我们分析脂多糖修饰如何响应环境条件进行调节。我们还将确定在发病机制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共同调节、反向调节或组成型转录。我们相信，这些研究将为了解宿主环境的生理适应与细菌细胞表面结构的协调生产之间的关系提供重要的见解，而细菌细胞表面结构对于与宿主细胞相互作用或逃避免疫反应至关重要。具体来说，我们将： 1. 表征参与 ChoP 细胞表面 LPS 修饰调节的氧化还原控制机制。 2. 研究流感嗜血杆菌中信号通路在上皮细胞相互作用和呼吸道感染模型中的作用。 3. 检查氧化还原信号系统对毒力因子的协调调节。