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: 8230727
• 负责人: Ashu Sharma
• 金额: $ 37.25万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230727
• 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）：Tannerella forsythia（Bacteroides forsythus）是革兰氏阴性的口服厌氧菌，涉及牙周疾病发病机理的发展。 T. forsythia仍然是最研究的牙周病原体之一，部分原因是培养这种细菌的生长需求以及对这种生物的遗传操纵的事实，直到最近才实现。此外，该生物在动物模型中的致病性直到最近才记录在案。我们在T. forsythia中确定了与表面相关的和分泌的蛋白BSPA。 BSPA蛋白属于富含亮氨酸的重复以及蛋白质的细菌免疫球蛋白样超家族。利用体外模型系统的研究表明，BSPA蛋白通过激活TOLL-HODER-FOLL-FOLL-FOLL-OFFOR-受体2诱导促炎细胞因子/趋化因子的释放，以及使细菌能够通过激活细胞内信号导致细胞骨架变化来激活细胞内信号，从而释放细菌。此外，BSPA介导了t. forsythia t. treponema denticola和fusobacterium nucleatum的凝聚。在细菌诱导的肺泡骨损失的小鼠模型中的研究表明，BSPA缺陷的T. forsythia突变体是无毒的，这表明BSPA是T. forsythia的重要毒力因子。该建议具有以下特定目标。 AIM 1针对：通过Toll样受体2信号传导，BSPA诱导的先天反应激活的表征； BSPA蛋白的结构功能研究，以及；鉴定细胞受体，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，将研究BSPA基因表达的调节机制。在AIM 2中，将在鼠模型中评估BSPA蛋白相对于定植和炎症的体内作用。此外，将确定牙周炎患者中对BSPA蛋白的免疫反应，以解决BSPA在发病机理中的重要性。这些方法对于确定BSPA蛋白在定植以及炎症中的作用将很重要。从长远来看，了解BSPA蛋白在发病机理和潜在机制中的作用对于开发针对牙周疾病的新型干预策略至关重要。坦纳氏菌Forsythia是一种革兰氏阴性的口腔厌食症，与牙周疾病发病发生有关，并且是牙周病发育的发展，并且是最宣告的牙周牙周牙周牙周病。该细菌表达与细胞表面相关的和分泌的毒力因子BSPA蛋白，该蛋白已被证明在细菌致病性中起重要作用。本应用中提出的研究旨在了解牙周疾病中BSPA诱导的发病机理的机制，并且对未来针对牙周疾病的治疗策略至关重要。