The role of oral spirochete virulence factors in the impairment of neutrophil response

口腔螺旋体在龈下牙菌斑中以高丰度存在， 严重的牙周损伤。牙周炎影响高达47%的美国人口， 某种形式。齿垢密螺旋体和其他口腔密螺旋体物种在口腔中定植并繁殖。 牙菌斑-牙龈组织界面，与中性粒细胞密切相关， 免疫细胞参与牙龈组织宿主反应。主要外鞘蛋白 (Msp)是由齿垢密螺旋体产生的主要毒力因子， 通过调节负责启动中性粒细胞趋化性的脂质代谢物， 在Msp蛋白中的活性表位介导的趋化过程。许多细菌病原体 包括口腔螺旋体已知产生外膜囊泡（OMV 许多细菌成分;包括致病性膜蛋白，如Msp。OMV是 现在也被认为是在感染过程中积极产生的毒力因子的有效包 由于它们的小尺寸和特性，具有局部和深远的致病作用; 在细菌存活和调节宿主反应中的关键作用。然而，仍然有一个 Msp在体内的作用以及功能和生物学方面的知识存在重大差距， 其他口腔密螺旋体和OMV在操纵中性粒细胞免疫中的作用 反应同样地，缺乏针对关键性的有效治疗分子。 螺旋体毒力因子我们的中心假设是口腔螺旋体介导的损害 通过具有共同功能特性的毒力因子发挥中性粒细胞功能。我们将测试 我们的假设通过完成以下具体目标：1。确定T. 啮齿动物模型中调节中性粒细胞功能的活性表位 炎症和牙周病2.评估未充分研究的口腔粘膜中的Msp样蛋白 螺旋体作为新的毒力因子损害中性粒细胞功能和3.评估生物成因 T.齿垢OMV是损害中性粒细胞功能的主要毒力因子。这项工作将 通过检查螺旋体的常见功能， Msp蛋白跨口腔密螺旋体物种，提供了新的见解OMV的贡献 以及Msp在OMV功能和与中性粒细胞相互作用中的作用。此外，我们还建议 开发针对Msp的潜在治疗试剂。了解如何口头 螺旋体毒力因子使中性粒细胞免疫应答无效， 开发新的治疗工具来预防这种情况，对改善口腔健康至关重要。 !

Oral spirochetes are present at high abundance in the subgingival dental plaque associated with severe periodontal lesions. Periodontitis affects up to 47% of the United States population in some form. Treponema denticola and other oral Treponema species colonize and thrive at the plaque-gingival tissue interface, in close association with neutrophils, the primary innate immune cells involved in the gingival tissue host response. The major outer sheath protein (Msp) is a prominent virulence factor produced by Treponema denticola that directly impairs neutrophil chemotaxis in vitro by modulation of lipid metabolites responsible for initiating the chemotactic process, mediated by active epitopes in the Msp protein. Many bacterial pathogens including oral spirochetes are known to produce outer membrane vesicles (OMVs) loaded with many bacterial components; including pathogenic membrane protein, such as Msp. OMVs are also now recognized as potent packages of virulence factors actively produced during infection with local and far-reaching pathogenic effects due to their small size and properties; which play key roles in bacterial survival and modulation of host response. However, there is still a significant gap in knowledge of the role of Msp in vivo as well as the functional and biological contribution of other oral Treponema species and OMVs in manipulating the neutrophil immune response. Likewise, there is a lack of efficient therapeutic molecules directed towards crucial spirochete virulence factors. Our central hypothesis is that oral spirochetes mediate impairment of neutrophil function through virulence factors with common functional properties. We will test our hypothesis by completion of the following specific aims: 1. Determine the potential of T. denticola Msp and the active epitopes to modulate neutrophil function in rodent-models of inflammation and periodontal disease 2. Assess Msp-like proteins from understudied oral spirochetes as novel virulence factors to impair neutrophil function and 3. Assess biogenesis of T. denticola OMVs as prominent virulence factors to impair neutrophil function. This work will advance our understanding of spirochete pathogenicity by examining common functionality of Msp proteins across oral treponema species, provide novel insight into the contribution of OMVs and the role of Msp in OMV function and interaction with neutrophils. Further, we also propose to develop potential therapeutic reagents directed towards Msp. Understanding how oral spirochete virulence factors render the neutrophil immune response ineffective and development of novel therapeutic tools to prevent this, is crucial to improving oral health. !