Global regulatory interactions in bacterial pathogenesis

性状（由申请方提供）：流感嗜血杆菌可有效地长期定植于人鼻咽粘膜，并能引起侵袭性疾病，包括中耳炎、肺炎和脑膜炎（更罕见）。H.流感病毒的毒力在前基因组时代就已被鉴定。利用基因组序列和新技术的出现，如全球表达谱分析，我们打算推进对这种生物体的关键毒力特征的理解。脂多糖（LPS）结构修饰是H.流感。使用表达谱与DNA微阵列，辅以经典的方法，我们最近发现了一个以前不受重视的氧化还原调节和LPS修饰之间的联系，在H。流感。此外，我们还在H.流感病毒破坏了对一种这样的修饰的氧化还原控制（向LPS添加磷酸胆碱表位，称为ChoP），并且还导致H.流感感染。这些观察结果是潜在的意义，在体内的LPS结构的环境信号的调制。我们建议使用我们实验室产生的这种信号和调节突变体来研究氧化还原信号在控制H.流感。我们已经开发了用于H.流感病毒将有助于我们分析LPS修饰如何响应环境条件而调节。我们还将确定是否在发病机制中发挥作用的其他基因的共调节，反向调节，或组成性转录的影响LPS修饰的各种氧化还原条件下。我们相信，这些研究将提供重要的见解宿主环境的生理适应和协调生产的细菌细胞表面结构与宿主细胞的相互作用或逃避免疫反应的关键之间的关系。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.研究信号通路在H.在上皮细胞相互作用的背景下和在呼吸道感染的模型中的流感。3.通过氧化还原信号系统检查毒力因子的协调调节。

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.