Group B. Streptococci and Toll-like Receptors

B 组链球菌和 Toll 样受体

• 批准号: 6541489
• 负责人: Douglas T Golenbock
• 金额: $ 41.42万
• 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: 2002-08-15 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6541489
• 关键词: SDS polyacrylamide gel electrophoresis; Streptococcus agalactiae; Streptococcus infection; bacteria infection mechanism; bacterial toxins; binding sites; biological signal transduction; cell line; chemotaxis; flow cytometry; gene deletion mutation; gene targeting; genetically modified animals; host organism interaction; laboratory mouse; leukocyte activation /transformation; molecular cloning; nuclear factor kappa beta; nucleic acid sequence; protein protein interaction; protein structure function; receptor binding; receptor expression; site directed mutagenesis; toll like receptor; transfection /expression vector

DESCRIPTION (provided by applicant): Group B streptococci (GBS) are the leading cause of neonatal sepsis, the third most frequent cause of bacterial meningitis and an increasingly important cause of bacteremia and sepsis in adults in the United States today. Preliminary studies have identified a novel proinflammatory component of GBS, which we have designated GBS-factor (GBS-F). Based on experiments in mice with targeted genetic deletions in Toll-like receptor (TLR) expression and on experiments with engineered cell lines, we have determined that responses to GBS-F require expression of CD14, TLRs 2 and 6, and the Toll-adapter protein, MyD88. Activation of this receptor complex by GBS-F initiates important signaling events such as the activation of NF-kB, the phosphorylation of MAP kinases, the formation of proinflammatory cytokines, and the intracellular production of the toxic oxidant peroxynitrate. In contrast, although other components of GBS appear to engage TLRs, the exact identity of contributing TLRs is entirely unknown. The overall goal of this proposal is to identify and define components of GBS, focusing first on GBS-F, and their cognate Toll-like receptors (TLRs). We propose to characterize the structure of GBS-F and assess its function in vitro and in vivo. Furthermore, we will determine if TLR2, and related downstream signal transduction molecules, mediate a variety of important innate immune responses to GBS, including leukocyte chemotaxis and the intracellular killing of bacteria. Finally, we intend to determine what other TLRs, and associated signal transduction molecules, are involved in GBS recognition and response. The data learned from these studies should help in the development of rational therapeutic strategies to interfere with the deleterious hyperinflammation triggered by GBS and similar microbial organisms.

描述（由申请人提供）：B组链球菌（GBS）是新生儿败血症的主要原因，是细菌性脑膜炎的第三大常见原因，也是当今美国成人菌血症和败血症的日益重要的原因。初步研究已经确定了GBS的新型促炎成分，我们已指定为GBS因子（GBS-F）。基于在Toll样受体（TLR）表达中具有靶向遗传缺失的小鼠的实验以及在具有工程细胞系的实验中，我们确定对GBS-F的反应需要CD14，TLRS 2和6的表达，以及Toll-Adapter蛋白MyD88。 GBS-F激活该受体复合物会引起重要的信号事件，例如NF-KB的激活，MAP激酶的磷酸化，促炎细胞因子的形成以及毒性氧化剂过氧二硝酸盐的细胞内产生。相反，尽管GB的其他组件似乎吸引了TLR，但贡献TLR的确切身份是完全未知的。该提案的总体目标是识别和定义GBS的组成部分，首先关注GBS-F及其同源收费受体（TLR）。我们建议表征GBS-F的结构并在体外和体内评估其功能。此外，我们将确定TLR2和相关的下游信号转导分子是否介导了各种对GBS的重要先天免疫反应，包括白细胞趋化性和细胞内细菌的细胞内杀死。最后，我们打算确定其他TLR和相关的信号转导分子涉及GBS识别和响应。从这些研究中学到的数据应有助于制定理性的治疗策略，以干扰GBS和类似微生物触发的有害高炎症。