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

口腔螺旋体毒力因子在中性粒细胞反应受损中的作用

• 批准号: 9981419
• 负责人: Michelle B Visser
• 金额: $ 37.88万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981419
• 关键词: Affect; Affinity; Alveolar Bone Loss; Bacteria; Biogenesis; Biological; Biology; C-terminal; Cells; Chemotaxis; Chronic; Cytokine Network Pathway; Data; Dental Plaque; Development; Disease Progression; Elements; Epitopes; Exposure to; Genetic Structures; Gingiva; Health; Homologous Gene; Homologous Protein; Immune; Immune response; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Knowledge; Lesion; Light; Lipids; Mediating; Membrane; Membrane Proteins; Metabolism; Modeling; Monoclonal Antibodies; N-terminal; Neutrophil Infiltration; Oral; Oral cavity; Oral health; Order Spirochaetales; Outcome; Pathogenicity; Periodontal Diseases; Periodontitis; Periodontium; Phosphatidylinositols; Play; Population; Process; Production; Property; Proteins; Proteomics; Reagent; Recombinant Proteins; Recombinants; Rodent Model; Role; Signal Pathway; Signal Transduction; Sorting - Cell Movement; Structure; Tertiary Protein Structure; Testing; Therapeutic; Tissues; Tooth Loss; Treponema; Treponema denticola; United States; Vesicle; Virulence Factors; Work; bacterial genetics; cytokine; design; improved; in vitro Model; in vivo; innovation; insight; lipid metabolism; migration; mouse model; mutant; neutrophil; novel; novel therapeutic intervention; novel therapeutics; oral infection; oral spirochetes; pathogenic bacteria; prevent; protein expression; protein function; protein structure function; response; tool

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. !

口腔螺旋体在与牙周炎有关的牙菌斑中大量存在 严重的牙周病变。牙周炎影响高达47%的美国人口 某种形式。齿密螺旋体和其他口腔密螺旋体物种在 菌斑-牙龈组织界面，与中性粒细胞密切相关，中性粒细胞是主要的先天 免疫细胞参与牙龈组织的宿主反应。主要的外鞘蛋白 (MSP)是齿密螺旋体产生的一种重要的毒力因子，直接损害 中性粒细胞在体外通过调节脂代谢产物而趋化 趋化过程，由MSP蛋白中的活性表位介导。许多细菌病原体 包括口腔螺旋体在内，已知会产生外膜小泡(OMV)， 细菌成分众多；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活跃产生的毒力因子的有效包 由于其体积小，性质小，具有局部而深远的致病作用； 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 对MSP在体内的作用以及在功能和生物学上的作用的认识存在显著差距 其他口腔密螺旋体和OMV在调节中性粒细胞免疫中的作用 回应。同样，缺乏针对至关重要的有效治疗分子。 螺旋体毒力因子。我们的中心假设是口腔螺旋体介导了损伤。 通过具有共同功能特性的毒力因子来影响中性粒细胞的功能。我们将测试 我们的假设通过完成以下具体目标来实现：1.确定T。 齿状幼虫MSP及其活性表位对鼠中性粒细胞功能的调节作用 炎症和牙周病2.评估未被研究的口腔MSP样蛋白 螺旋体作为新的毒力因子损害中性粒细胞功能及3.评价螺旋体的生物发生 齿状毛滴虫OMVS是损害中性粒细胞功能的重要毒力因子。这项工作将 通过研究螺旋体的共同功能，促进我们对螺旋体致病性的理解 口腔密螺旋体物种中的MSP蛋白，为OMV的贡献提供了新的见解 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 目的：开发针对MSP的潜在治疗试剂。了解如何口头表达 螺旋体毒力因子使中性粒细胞免疫反应无效和 开发新的治疗工具来预防这种情况，对于改善口腔健康至关重要。 好了！