Tannerella forsythia intercations with host cells and other bacteria

描述（由申请方提供）：Tannerella pasthia（Bacteroides pasthus）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。T.该菌仍然是研究最不足的牙周病原体之一，部分原因是培养这种细菌的苛刻生长要求以及这种生物体的遗传操作最近才完成。此外，这种生物体在动物模型中的致病性最近才被记录下来。我们在T.艾西娅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已经表明，BspA蛋白通过激活toll样受体2诱导促炎细胞因子/趋化因子从宿主细胞中释放，以及通过激活导致细胞骨架变化的细胞内信号传导赋予细菌侵入上皮细胞的能力.此外，BspA介导T.梅毒合并齿垢密螺旋体和具核梭杆菌。在细菌诱导的牙槽骨丢失的小鼠模型中的研究表明，BspA缺陷的T。BspA是T.艾西娅该提案有以下具体目标。目标1是：通过Toll样受体2信号传导表征BspA诱导的先天性应答激活; 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，bspA基因表达的调控机制将进行研究。在目的2中，将在鼠模型中评估BspA蛋白相对于定殖和炎症的体内作用。此外，牙周炎患者对BspA蛋白的免疫应答将被确定，以解决BspA在发病机制中的重要性。这些方法在确定BspA蛋白在定殖以及炎症中的作用方面将是重要的。从长远来看，了解BspA蛋白在发病机制和潜在机制中的作用对于开发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，也是研究最少的牙周病原体之一。该细菌表达细胞表面相关的以及分泌的毒力因子，BspA蛋白，其已被证明在细菌致病性中起重要作用。本申请中提出的研究旨在了解BspA诱导的牙周病发病机制，并将在未来制定牙周病治疗策略中发挥重要作用。

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.