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Tannerella forsythia仍然是一种研究较少和神秘的生物，尽管临床证据越来越多地表明该生物与牙周炎有关。此外，近年来连翘也在牙髓感染和全身性疾病中被发现。繁殖这种细菌的困难，以及它对基因操作相当有抵抗力的事实，使这种细菌对研究人员的吸引力降低。连翘表达表征良好的TLR2配体、BspA蛋白以及构成其覆盖外膜的表面(S)层的N-和o -聚糖连接的糖蛋白。BspA蛋白和细菌聚糖在细菌毒力中起关键作用。具体来说，s层聚糖会影响抗原呈递细胞对细菌的识别，并改变它们的细胞因子表达，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，连翘BspA和其他配体诱导TLR2信号，有利于th2型炎症反应的发展，对牙槽骨有害。本应用的目的是了解连翘利用其表面聚糖和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)明确连翘s层聚糖与巨噬细胞和树突状细胞的相互作用及其导致宿主免疫调节的机制。我们将测试表面聚糖通过与凝集素样受体相互作用来调节细胞因子反应和这些细胞的功能的假设；(2)利用牙周炎小鼠模型确定tlr2 - th2轴在连翘诱导的牙槽骨丢失中的作用。我们将检验Th2极化触发增殖的假设