Tannerella forsythia intercations with host cells and other bacteria

连翘坦纳菌与宿主细胞和其他细菌的相互作用

• 批准号: 8033674
• 负责人: Ashu Sharma
• 金额: $ 36.5万
• 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 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8033674
• 关键词: Address; Alveolar Bone Loss; Animal Model; Antibodies; Bacteria; Bacteroides forsythus; Biological Models; Cell Line; Cell surface; Cells; Cytoskeleton; Development; Disease; Epithelial Cells; Epithelial Receptor Cell; Forsythia; Fusobacterium nucleatum; Future; Gene Expression; Genes; Gingiva; Growth; Human; Immune response; Immunoglobulins; In Vitro; Infection; Inflammation; Intervention; Invaded; KB Cells; Leucine-Rich Repeat; Light; Mediating; Modeling; Molecular; Mus; Organism; Pathogenesis; Pathogenicity; Patients; Pattern; Peptides; Periodontal Diseases; Periodontitis; Play; Promoter Regions; Proteins; Recording of previous events; Regulation; Relative (related person); Role; Serum; Signal Transduction; Stimulus; Structure; Surface; Testing; Therapeutic; Toll-Like Receptor 2; Treponema denticola; Virulence; Virulence Factors; base; chemokine; cytokine; genetic manipulation; immunogenicity; in vitro Model; in vivo; mouse model; mutant; novel; oral anaerobes; pathogen; receptor; response

DESCRIPTION (provided by applicant): Tannerella forsythia (Bacteroides forsythus) is a gram-negative oral anaerobe implicated in the development of periodontal disease pathogenesis. T. forsythia remains one of the most understudied periodontal pathogens, partly due to the fastidious growth requirements for culturing this bacterium as well as the fact that genetic manipulation of this organism has only recently been accomplished. Moreover, the pathogenicity of this organism in animal models has only been documented recently. We identified a surface-associated as well as a secreted protein, BspA, in T. forsythia. The BspA protein belongs to the leucine-rich-repeat as well as to the bacterial immunoglobulin-like superfamilies of proteins. Studies utilizing in vitro model systems have shown that the BspA protein induces the release of proinflammatory cytokines/chemokines from host cells by activating toll- like receptor 2, as well as confers bacteria the ability to invade epithelial cells by activating intracellular signaling leading to cytoskeleton changes. In addition, BspA mediates coaggregation of T. forsythia with Treponema denticola and Fusobacterium nucleatum. Studies in a mouse model of bacterially-induced alveolar bone loss showed that a BspA-defective T. forsythia mutant was avirulent, suggesting that BspA is an important virulence factor of T. forsythia. This proposal has following specific aims. Aim 1 is directed toward: characterization of BspA-induced activation of innate responses through toll-like receptor 2 signaling; structure function studies of the BspA protein, and; identification of the cellular receptor including intracellular signaling associated with BspA-mediated bacterial entry into epithelial cells. In addition, regulatory mechanisms of bspA gene expression will be investigated. In aim 2, in vivo role of BspA protein relative to colonization and inflammation will be evaluated in a murine model. Moreover, the immune response to the BspA protein in patients with periodontitis will be determined to address the importance of BspA in pathogenesis. These approaches will be important in determining the roles of the BspA protein in colonization as well as in inflammation. In the long term, understanding the role of the BspA protein in pathogenesis and underlying mechanisms will be vital in developing novel intervention strategies against periodontal disease.Tannerella forsythia is a gram-negative oral anaerobe implicated in the development of periodontal disease pathogenesis and is one of the most understudied periodontal pathogens. This bacterium expresses a cell surface-associated as well as secreted virulence factor, the BspA protein, which has been shown to play important roles in the bacterial pathogenicity. The studies proposed in this application are aimed at understanding the mechanisms of BspA-induced pathogenesis in periodontal disease and will be vital in developing therapeutic strategies against periodontal diseases in future.

描述（由申请人提供）：福赛坦纳菌（Bacteroides forsythus）是一种革兰氏阴性口腔厌氧菌，与牙周病发病机制的发展有关。连翘仍然是研究最多的牙周病原体之一，部分原因是培养这种细菌的生长要求严格，而且该生物体的基因操作最近才完成。此外，这种生物体在动物模型中的致病性直到最近才被记录。我们在连翘中鉴定出了一种表面相关蛋白和一种分泌蛋白 BspA。 BspA 蛋白属于富含亮氨酸的重复序列以及细菌免疫球蛋白样蛋白超家族。利用体外模型系统的研究表明，BspA 蛋白通过激活 Toll 样受体 2 诱导宿主细胞释放促炎细胞因子/趋化因子，并通过激活细胞内信号传导导致细胞骨架变化，赋予细菌侵入上皮细胞的能力。此外，BspA 介导连翘连翘与齿垢密螺旋体和具核梭杆菌的共聚集。对细菌引起的牙槽骨丢失的小鼠模型的研究表明，BspA 缺陷的连翘突变体是无毒的，这表明 BspA 是连翘的重要毒力因子。该提案有以下具体目标。目标 1 旨在：表征 BspA 通过 Toll 样受体 2 信号传导诱导的先天反应激活； BspA 蛋白的结构功能研究；细胞受体的鉴定，包括与 BspA 介导的细菌进入上皮细胞相关的细胞内信号传导。此外，还将研究bspA基因表达的调控机制。在目标 2 中，将在小鼠模型中评估 BspA 蛋白相对于定植和炎症的体内作用。此外，将确定牙周炎患者对 BspA 蛋白的免疫反应，以阐明 BspA 在发病机制中的重要性。这些方法对于确定 BspA 蛋白在定植和炎症中的作用非常重要。从长远来看，了解 BspA 蛋白在发病机制中的作用和潜在机制对于制定针对牙周病的新型干预策略至关重要。福赛坦纳菌是一种革兰氏阴性口腔厌氧菌，与牙周病发病机制的发展有关，是牙周病发病机制之一。研究最多的牙周病原体。这种细菌表达细胞表面相关以及分泌的毒力因子 BspA 蛋白，该蛋白已被证明在细菌致病性中发挥重要作用。本申请提出的研究旨在了解 BspA 诱导的牙周病发病机制，对于未来制定针对牙周病的治疗策略至关重要。