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

基本信息

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
项目类别：
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

项目摘要

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，连翘坦纳菌仍然是一种研究较少且神秘的生物体，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，连翘连翘也在牙髓感染中被发现，并与全身性疾病有关。这种细菌繁殖困难，而且它对基因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。连翘表达特征明确的 TLR2 配体、BspA 蛋白以及 N- 和 O- 聚糖连接的糖蛋白，这些糖蛋白构成其覆盖外膜的表面 (S) 层。 BspA 蛋白和细菌聚糖在细菌毒力中发挥着关键作用。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。这导致细菌在宿主体内的持久性和定殖增加。同时，BspA 和连翘的其他配体诱导 TLR2 信号传导，有利于 Th2 型炎症反应的发展，对牙槽骨有害。本申请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，我们建议：（1）定义连翘S层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。我们将测试以下假设：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； (2)使用牙周炎小鼠模型确定TLR2-Th2轴如何导致连翘诱导的牙槽骨丢失。我们将检验 Th2 极化触发增殖的假设表达 RANKL 的 B 细胞，最终导致牙槽骨丢失。因此，我们的研究将详细描述连翘诱导的牙周炎症期间TLR2与细菌配体和S层糖蛋白连接协调宿主免疫的潜在机制，这对于未来牙周炎预防策略的发展至关重要。