Treponema denticola-Innate Immune System Interactions

齿垢密螺旋体与先天免疫系统的相互作用

• 批准号: 6985132
• 负责人: JOHN Dawson RUBY
• 金额: $ 7.27万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6985132
• 关键词: Treponema; Treponema infection; bacteria infection mechanism; bacterial proteins; bacterial somatic antigen; bactericidal immunity; flagellum; genetically modified animals; immune response; laboratory mouse; mutant; oral bacteria; toll like receptor

DESCRIPTION (provided by applicant): T. denticola is an important periodontal pathogen. The cellular mechanisms responsible for the recognition of T. denticola by the innate immune system are not currently resolved. Our long-term goal is to elucidate the cellular receptors of the host responsible for the recognition of T. denticola, as well as its periplasmic flagella (PFs) and major surface protein (Msp) by the innate immune system and how the engagement of the TLR pathways are regulating the inflammatory response. Our hypothesis is: the ability of T. denticola whole cells, PFs, and Msp to interact with Toll-like receptors (TLRs), specifically TLR2, expressed on immune cells is a major mechanism responsible for the pathogenesis of this organism by regulating the induction, nature, and magnitude of the host's inflammatory response. This hypothesis is based on 1) a direct comparison of immune cells isolated from wild-type and TLR2-deficient mice demonstrated that the levels of the pro-inflammatory cytokine, TNF-alpha was significantly different when stimulated with T. denticola, 2) stimulation of immune cells from TLR2-deficient mice with T. denticola did not result in detectable levels of TNF-alpha production; thus demonstrating that TLR2 is responsible for mediating innate immune responses to T. denticola whole cells; 3) stimulation of wild-type and TLR4-deficient cells with T. denticola resulted in similar levels of TNF-alpha; thus demonstrating that TLR4 is not involved in mediating cellular responses to T. denticola; 4) isogenic mutants HL51 (lacks PFs) and MHE (lacks Msp) had >60% and 30% reduction in TNF-alpha levels, respectively, as compared to wild-type T. denticola cells. These experimental observations have led to the basis of the current proposal to focus on the specific role of TLR2 in mediating the host's innate immune response to T. denticola. We propose to characterize the functional ability of TLR2 (in conjunction with TLR1, TLR6, or both) to mediate the production of pro- and anti-inflammatory cytokine production in response to T. denticola, its PFs and Msp. Specifically, with the aid of TLR-(initially 1, 2, and 6) knockout mice: (a) we will determine how TLR2 is involved in mediating cellular responses to T. denticola and its isogenic mutants HL51 and MHE; and (b) identify how these specific factors associated with T. denticola, e.g. PFs and Msp, mediate host inflammatory responses.

描述（由申请人提供）：T. denticola 是一种重要的牙周病原体。先天免疫系统识别齿垢毛虫的细胞机制目前尚未解决。我们的长期目标是阐明负责先天免疫系统识别 T. denticola 及其周质鞭毛 (PF) 和主要表面蛋白 (Msp) 的宿主细胞受体，以及如何参与TLR 通路调节炎症反应。我们的假设是：T. denticola 全细胞、PF 和 Msp 与免疫细胞上表达的 Toll 样受体 (TLR)（特别是 TLR2）相互作用的能力是通过调节诱导而导致该生物体发病的主要机制。宿主炎症反应的性质和程度。这一假设基于 1) 对从野生型和 TLR2 缺陷型小鼠中分离出的免疫细胞进行直接比较，结果表明，当用 T. denticola 刺激时，促炎细胞因子 TNF-α 的水平显着不同，2)来自 TLR2 缺陷小鼠的免疫细胞与 T. denticola 的免疫细胞没有导致可检测水平的 TNF-α 产生；从而证明 TLR2 负责介导针对 T. denticola 全细胞的先天免疫反应； 3) 用 T. denticola 刺激野生型和 TLR4 缺陷细胞，产生相似的 TNF-α 水平；从而证明 TLR4 不参与介导对齿垢毛虫的细胞反应； 4) 与野生型齿垢T. denticola细胞相比，同基因突变体HL51（缺乏PF）和MHE（缺乏Msp）的TNF-α水平分别降低>60%和30%。这些实验观察结果为当前提议的基础奠定了基础，即重点关注 TLR2 在介导宿主对齿垢毛虫的先天免疫反应中的特定作用。我们建议表征 TLR2（与 TLR1、TLR6 或两者结合）介导响应 T. denticola、其 PF 和 Msp 的促炎和抗炎细胞因子产生的功能能力。具体来说，在 TLR-（最初为 1、2 和 6）敲除小鼠的帮助下：（a）我们将确定 TLR2 如何参与介导对 T. denticola 及其同基因突变体 HL51 和 MHE 的细胞反应； (b) 确定这些特定因素如何与 T. denticola 相关，例如PFs 和 Msp 介导宿主炎症反应。