T. forsythia TLR2 ligands and surface glycans coordinate periodontal inflammation

连翘 TLR2 配体和表面聚糖协调牙周炎症

• 批准号: 9296119
• 负责人: Ashu Sharma
• 金额: $ 39.74万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9296119
• 关键词: Adult; Alveolar Bone Loss; Anaerobic Bacteria; Antigen-Presenting Cells; B-Lymphocytes; Bacteria; C Type Lectin Receptors; Cell physiology; Clinical; Dendritic Cells; Development; Disease; Endodontics; Forsythia; Future; Gingivitis; Glycoproteins; Grant; Immune; Immune response; Immune system; Immunity; Immunotherapy; Infection; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Lead; Lectin; Ligands; Ligation; Link; Lymphocyte antigen CD50; Mediating; Membrane; Mus; Neutrophil Infiltration; Organism; Outcome; Pathogenesis; Pattern recognition receptor; Periodontitis; Periodontium; Play; Polysaccharides; Predisposition; Prevention strategy; Proteins; Receptor Cell; Receptors, Antigen, B-Cell; Research Personnel; Resistance; Role; Signal Transduction; Structure; Surface; Systemic disease; TLR2 gene; Testing; Th2 Cells; Tissues; Tooth Loss; Vaccines; Variant; Virulence; Virulence Factors; alveolar bone; base; bone; cytokine; genetic manipulation; glycosylation; immunoregulation; improved; macrophage; mouse model; mutant; oral bacteria; osteoclastogenesis; pathogen; prevent; public health relevance; receptor; response

DESCRIPTION (provided by applicant): Tannerella forsythia remains a less studied and an enigmatic organism in comparison to other periodontal pathogens, even though clinical evidence increasingly implicates the organism in periodontitis. Additionally, in recent years T. forsythia has also been detected in endodontic infections and linked to systemic diseases. Difficulties in propagating this bacterium and the fact that it is quite resistant to genetic manipulations have made this bacterium less appealing to investigators. T. forsythia expresses a well- characterized TLR2 ligand, the BspA protein, and N- and O-glycan linked glycoproteins that comprise its surface (S) - layer, covering the outer membrane. The BspA protein and the bacterial glycans play critical roles in bacterial virulence. Specifically, S-layer glycans impact bacterial recognition by the antigen-presenting cells and modify their cytokine expression such that it results in the blockade of Th17 responses and neutrophil recruitment. This leads to increased bacterial persistence and colonization in the host. Concurrently, BspA and other ligands of T. forsythia induce TLR2 signaling favoring the development of Th2-type inflammatory responses detrimental to the alveolar bone. The aim of this application is to understand the mechanisms by which T. forsythia exploits its surface glycans and TLR2 ligands to induce alveolar bone loss. To achieve our aim we propose to: (1) Define the interactions of T. forsythia S-layer glycans with macrophages and dendritic cells and the mechanisms leading to host immune modulation. We will test the hypothesis that the surface glycans by interacting with lectin-like receptors regulate cytokine responses and function of these cells, and; (2) Determine how theTLR2-Th2 axis contributes to T. forsythia-induced alveolar bone loss using a periodontitis mouse model. We will test the hypothesis that Th2 polarization triggers proliferation of RANKL expressing B cells, which eventually contributes to alveolar bone loss. Thus, our studies will delineate in detail the underlying mechanisms by which TLR2 ligation by bacterial ligands and S-layer glycoproteins orchestrate host immunity during T. forsythia-induced periodontal inflammation and will be fundamental to the development of preventive strategies against periodontitis in the future.

描述(由申请人提供)：与其他牙周病原体相比，连翘坦纳氏菌仍然是一个研究较少的神秘生物体，尽管临床证据越来越多地表明该生物体与牙周炎有关。此外，近年来，在牙髓感染中也发现了连翘，并与系统性疾病有关。这种细菌很难繁殖，而且它对遗传操作具有很强的抵抗力，这使得这种细菌对研究人员的吸引力降低。连翘表达一个功能齐全的TLR2配体，BspA蛋白，以及组成其表层(S)的N-和O-葡聚糖连接的糖蛋白，覆盖在外膜上。BSPA蛋白和细菌多聚糖在细菌毒力中起着关键作用。具体地说，S层多聚糖影响抗原提呈细胞对细菌的识别，并改变其细胞因子的表达，从而导致Th17反应和中性粒细胞募集的阻断。这导致细菌在宿主中的持久性和定植增加。同时，BSPA和连翘的其他配体诱导TLR2信号，有利于Th2型炎症反应的发展，对牙槽骨不利。这项应用的目的是了解连翘利用其表面多糖和TLR2配体诱导牙槽骨丢失的机制。为了实现我们的目标，我们提出：(1)确定连翘S层多聚糖与巨噬细胞和树突状细胞的相互作用以及导致宿主免疫调节的机制。我们将通过与凝集素样受体的相互作用来检验表面多糖调节这些细胞的细胞因子反应和功能的假设；以及(2)使用牙周炎小鼠模型来确定TLR2-Th2轴如何促进连翘诱导的牙槽骨丢失。我们将检验Th2极化触发细胞增殖的假设 RANKL表达B细胞，最终导致牙槽骨丢失。因此，我们的研究将详细揭示在连翘诱导的牙周炎症过程中，细菌配体和S层糖蛋白连接TLR2对宿主免疫的调控机制，并将为今后牙周炎的预防策略的制定奠定基础。