Mechanisms of neutrophil impairment by Treponema denticola

 描述（由申请人提供）：齿垢密螺旋体是一种存在于与严重牙周病变相关的龈下牙菌斑中的口腔螺旋体。T.齿垢在牙斑-牙龈组织界面处与嗜中性粒细胞密切相关地定殖和繁殖，嗜中性粒细胞是对牙龈组织中宿主防御的第一道防线起作用的主要先天免疫细胞。主要外鞘蛋白（major outer sheath protein，Msp）是T.直接损害中性粒细胞功能包括定向迁移（趋化性）的齿垢。Msp通过调节启动迁移过程的磷脂信号分子的产生来损害中性粒细胞的趋化性。然而，对于T.齿垢Msp协调抑制中性粒细胞趋化性。我们的中心假设是T.齿垢Msp具有与整个Msp分子类似的功能区域，负责操纵磷脂修饰酶。我们将通过完成以下具体目标来检验我们的假设：1。鉴定Msp抑制中性粒细胞趋化性和相关信号通路的功能区域; 2.鉴定参与磷脂修饰酶失调的初始MSP介导的中性粒细胞信号传导事件。这一工作将进一步加深我们对T.通过鉴定参与嗜中性粒细胞逃避的初始磷脂相关信号事件和参与的Msp蛋白区域来确定齿垢病的致病性。了解口腔螺旋体毒力因子如何使中性粒细胞免疫反应无效，以允许持续的细菌存活是未来开发新治疗方法的关键。

 DESCRIPTION (provided by applicant): Treponema denticola is an oral spirochete present in the subgingival dental plaque associated with severe periodontal lesions. T. denticola colonizes and thrives at the plaque-gingival tissue interface, in close association with neutrophils, the primary innate immune cells contributing to the first line of host defense in the gingival tissue. The major outer sheath protein (Msp) is a prominent virulence factor of T. denticola that directly impairs neutrophil function including directed migration (chemotaxis). Msp impairs neutrophil chemotaxis by modulating the production of phospholipid signalling molecules that initiate the migratory process. However, there is still a significant gap in knowledge of how T. denticola Msp orchestrates inhibition of neutrophil chemotaxis. Our central hypothesis is that T. denticola Msp possesses functional regions that similarly to the entire Msp molecule, are responsible for manipulation of phospholipid modifying enzymes. We will test our hypothesis by completion of the following specific aims: 1. Identify the functional regions of Msp that inhibit neutrophil chemotaxis and associated signalling pathways and 2. Identify initial Msp-mediated neutrophil signalling events involved in dysregulation of phospholipid modifying enzymes. This work will advance our understanding of T. denticola pathogenicity through identification of initial phospholipid- related signalling events involved in neutrophil evasion and Msp protein regions involved. Understanding how oral spirochete virulence factors render the neutrophil immune response ineffective to allow for sustained bacterial survival is key to future development of new therapeutic approaches.