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。牙本质是重要的牙周病原体。目前尚未解决，先天免疫系统识别牙霉菌的细胞机制尚未解决。我们的长期目标是通过先天免疫系统以及TLR途径如何调节炎症反应。我们的假设是：牙霉菌全细胞，PFS和MSP与Toll样受体（TLRS）相互作用（特异性TLR2）在免疫细胞上表达的能力是导致这种生物体发病机理的主要机制，通过调节宿主炎症反应的诱导，性质和大小。该假设基于1）直接比较从野生型和TLR2缺陷的小鼠中分离出的免疫细胞，表明，促炎性细胞因子的水平TNF-α的水平显着差异，当用T. denticola刺激T. denticola，2）从TLR2缺乏小鼠中刺激TLR2缺乏型T. dendicola dendicola时，TNF-alpha的水平显着差异。 TNF-Alpha生产；因此，表明TLR2负责介导对牙霉菌全细胞的先天免疫反应。 3）用牙霉菌刺激野生型和TLR4缺陷型细胞，导致TNF-Alpha水平相似；因此，表明TLR4不参与介导细胞对牙霉菌的反应。 4）与野生型T. denticola细胞相比，ISENIC突变体HL51（缺乏PFS）和MHE（缺乏MSP）的TNF-Alpha水平分别降低了60％和30％。这些实验观察结果导致了当前的提议，即关注TLR2在介导宿主对牙霉菌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）的功能能力，以介导对T. denticola（其PFS和MSP）的促疾病和抗炎细胞因子产生的产生。具体而言，借助TLR-（最初为1、2和6）基因敲除小鼠：（a）我们将确定TLR2如何参与介导对牙齿齿状球杆菌及其同基因突变体HL51和MHE的细胞反应； （b）确定这些特定因素如何与牙霉菌相关，例如PFS和MSP，介导宿主炎症反应。