Treponema denticola cytoskeletal filaments and oral infection

齿垢密螺旋体细胞骨架丝与口腔感染

基本信息

批准号：
7253018
负责人：
JACQUES G. IZARD
金额：
$ 24.11万
依托单位：
ADA FORSYTH INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7253018
关键词：
Affect Animal Model Antigen Presentation Bacteria Bacterial Infections Basic Science Biology Bone Resorption Bone Tissue Cell-Matrix Junction Cells Class Clinical Cytoplasmic Filaments Cytoplasmic Structures Cytoskeletal Filaments Data Development Disease Outcome Disease Progression Disease model End Point Endodontics Engineering Event Filament Formalin Future Genetic Engineering Gingivitis Goals Grant Healed Histology Human Immune response In Vitro Infection Inflammation Interleukin-10 Intermediate Filaments Invasive Knock-out Life Measurement Membrane Methodology Microbial Biofilms Modeling Modification Mouse Strains Mus Nature Oral Organism Outcome Pathogenesis Pathogenicity Patients Penetration Periodontal Diseases Periodontal Infection Periodontitis Phase Plant Roots Population Population Analysis Population Process Predisposition Process Production Proteins Research Ribosomal RNA Role Site Structure Testing Tissues Tooth Cervix Tooth structure Toxin Translational Research Treponema Treponema denticola Work alveolar bone base bone loss cell motility cell type cytokine experience fighting healing in vivo killings microbial mouse model mutant oral biofilm oral infection oral pathogen oral spirochetes pathogen periplasm pressure prevent research study tool

Affect Animal Model Antigen Presentation Bacteria Bacterial Infections Basic Science Biology Bone Resorption Bone Tissue Cell-Matrix Junction Cells Class Clinical Cytoplasmic Filaments Cytoplasmic Structures Cytoskeletal Filaments Data Development Disease Outcome Disease Progression Disease model End Point Endodontics Engineering Event Filament Formalin Future Genetic Engineering Gingivitis Goals Grant Healed Histology Human Immune response In Vitro Infection Inflammation Interleukin-10 Intermediate Filaments Invasive Knock-out Life Measurement Membrane Methodology Microbial Biofilms Modeling Modification Mouse Strains Mus Nature Oral Organism Outcome Pathogenesis Pathogenicity Patients Penetration Periodontal Diseases Periodontal Infection Periodontitis Phase Plant Roots Population Population Analysis Population Process Predisposition Process Production Proteins Research Ribosomal RNA Role Site Structure Testing Tissues Tooth Cervix Tooth structure Toxin Translational Research Treponema Treponema denticola Work alveolar bone base bone loss cell motility cell type cytokine experience fighting healing in vivo killings microbial mouse model mutant oral biofilm oral infection oral pathogen oral spirochetes pathogen periplasm pressure prevent research study tool

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项目摘要

DESCRIPTION (provided by applicant): Among the key pathogens involved in oral bacterial diseases, Treponema denticola is the most invasive organism. The various oral Treponema bacterial species have in common a cytoplasmic structure with organizational similarities to intermediate filaments. In vitro experiments have demonstrated the importance of such structure in key events related to oral infectivity. The goal of this research is to decipher the importance and function of treponemal intermediate-like filaments in pathogenicity in vivo. The long-term goal is to develop new strategies to combat the invasive nature of treponemal cells, while maintaining a healthy oral microbiota. The rationale is to validate the hypothesis that treponemes propagation (colonization, persistence, and dissemination first local and then systemic) is dependent upon intermediate- like filaments. The proposed studies will focus on testing the pathogenicity of a genetically engineered T. denticola mutant deficient in intermediate-like filaments (cfpA knockout) in appropriate animal models to study oral infections. The infectivity of the cfpA knockout mutant will be tested in two mouse models. The first mouse model investigates the tissue and bone damage associated with an endodontic infection (Aim 1). The second mouse model tests the pathogenicity in a periodontal infection (Aim 2). In conjunction with the cfpA knockout mutant, the wild-type strain (live and formalin-killed) will be used as control, as well as a mutant deficient in motility to test the effect of live antigen presentation during the colonization step. The experimental quantitative endpoint is the measurement of bone loss at the root of the infected tooth in the endodontic model, and the recession of the alveolar bone crest from the cementoenamel junction in the periodontal model. A qualitative criterion is the inflammation associated with the infection, which is to be evaluated by histology of the center plane of the infected tooth in the endodontic infection model, and by cytokine production in the periodontal infection model. In the case of the periodontal infection model, an additional criterion will be the modification of the oral microbiota post-infection. This study will further our understanding of the pathogenesis of T. denticola in both periodontal and endodontic infections by providing a more complete understanding of the role of intermediate-like filaments in infectivity, the importance of motility for treponemes persistence, and model the biofilm population changes associated with periodontal disease. To allow the modulation of the oral biofilm, clinicians need new strategies to fight periodontal diseases. New strategies rely on an understanding of microbial biology. To limit bone loss and other damages, proper host responses and healthy natural biofilm should be promoted in the patient healing process. Our strategy is to target key functional entities of aggressive and invasive pathogens, with the goal of eliminating the damage- inducing population.

描述（由申请人提供）：在与口腔细菌疾病有关的关键病原体中，treponema denticola是最具侵入性的生物。各种口服毛毛虫细菌物种具有与中间细丝的组织相似性的胞质结构。体外实验证明了这种结构在与口服感染性有关的关键事件中的重要性。这项研究的目的是破译体内发病中间类细丝的重要性和功能。长期目标是制定新的策略，以抵抗毛毛细胞的侵入性，同时保持健康的口腔微生物群。基本原理是验证treponemes繁殖（定殖，持久性和传播首先局部，然后是全身性）的假设取决于中间的细丝。拟议的研究将着重于测试遗传工程的T.牙粘菌突变体在适当的动物模型中缺乏中等样细丝（CFPA敲除）的致病性，以研究口腔感染。 CFPA敲除突变体的感染性将在两个小鼠模型中进行测试。第一个小鼠模型研究了与牙髓感染相关的组织和骨损伤（AIM 1）。第二小鼠模型测试牙周感染中的致病性（AIM 2）。结合CFPA敲除突变体，野生型菌株（活和福尔马林杀伤）将用作对照，以及在定殖步骤期间活跃的突变体的运动性不足以测试活抗原表现的效果。实验定量终点是牙髓模型中受感染牙根的骨质流失的测量，以及牙周模型中牙胶烯胺连接的肺泡骨冠的衰退。定性标准是与感染相关的炎症，该炎症应在牙髓感染模型中通过感染牙齿的中心平面的组织学评估，以及牙周感染模型中的细胞因子产生。在牙周感染模型的情况下，感染后口服微生物群的修饰将是一个附加标准。这项研究将进一步理解牙霉菌在牙周和牙髓感染中的发病机理，通过对中间样细丝在感染性中的作用，treponemes持久性的重要性以及与周期性疾病相关的生物膜种群变化进行建模，从而更完整地了解中间样细丝在感染性中的作用。为了调节口腔生物膜，临床医生需要新的策略来抵抗牙周疾病。新策略依赖于对微生物生物学的理解。为了限制骨质流失和其他损害，应在患者康复过程中促进适当的宿主反应和健康的自然生物膜。我们的策略是针对侵略性和侵入性病原体的关键功能实体，目的是消除造成损害的人群。