Exploring new virulence factors of the oral spirochete Treponema denticola

摘要(父级授予) 先天免疫系统(即补体和中性粒细胞介导的杀伤)是第一道防线。 对抗微生物感染。在口腔中，先天免疫系统高度活跃并维持 共生阶段的口腔微生物区系。作为一种关键病原体，口腔密螺旋体 齿状突起(TD)是高度侵袭性的，在其所在的牙周下菌斑中确立了自己的地位 直接面对宿主的免疫反应。TD能够突破宿主的免疫防御，存活下来， 甚至在生物失调和炎症恶化时(例如，在严重的 和顽固性牙周炎)。TD逃避宿主免疫的潜在机制 对此的回应在很大程度上仍不得而知。在上一个资金周期中，我们发现了几个新颖的 TD中的毒力因子。在这些因素中，我们发现TDE0362(一种半胱氨酸蛋白酶)和 TDE0471是一种唾液酸酶，具有独特的生化和结构特征，保护TD免受补体的侵害 和中性粒细胞的杀伤，并在TD的致病性中起关键作用。我们还确认了一部小说 修饰TD鞭毛蛋白的多糖，这种独特的修饰不仅对 TD的鞭毛和运动性也改变了对鞭毛的先天免疫反应。建立在 这些发现，这一更新旨在阐明这三个小说背后的分子机制 TD的致病特性。为了实现这一目标，将解决以下三个问题。(1)什么 TDE0362损害宿主中性粒细胞和补体激活的分子机制吗？(2) TDE0471如何利用宿主唾液酸保护TD免受补体杀伤？(3)如何 糖基化改变TD鞭毛蛋白的先天免疫反应？完成这些研究将不会 不仅为在分子水平上理解TD的致病性提供了新的见解，而且还 提高我们目前对牙周炎的独特性和复杂性的理解。其中一个独特的 Keystone病原体的一些方面是，虽然它们引发了强烈和敌意的炎症，但它们 也进化出复杂的机制来逃避宿主的免疫防御，这使得它们能够在 口袋里，将共生微生物区系改变为生物多样性，并造成组织损伤。了解他们的 其独特性和潜在的机制将导致新的治疗和预防牙周炎的策略。

Abstract (Parent Grant) The innate immune system (i.e., complement- and neutrophil-mediated killing) is the first line of defense against microbial infections. In the oral cavity, the innate immune system is highly active and sustains the oral microbiota at the stage of symbiosis. As a keystone pathogen, the oral bacterium Treponema denticola (Td) is highly invasive, establishing itself at the forefront of subgingival plaques where it directly confronts the host immune response. Td is able to breach host immune defenses, survives, and even becomes predominant in the pocket when dysbiosis and inflammation worsens (e.g., in severe and refractory periodontitis). The underlying mechanisms that allow Td to evade the host immune response remain largely unknown. During the last funding cycle, we have discovered several novel virulence factors in Td. Among these factors, we found that TDE0362 (a cysteine protease) and TDE0471 (a sialidase) have unique biochemical and structural features, protect Td from complement and neutrophils killings, and play pivotal roles in the pathogenicity of Td. We also identified a novel glycan that modifies Td flagellin proteins and this unique modification is not only essential for the flagellation and motility of Td but also alters the innate immune response to the flagellins. Building upon these findings, this renewal aims to elucidate the molecular mechanisms underlying these three novel pathogenic traits of Td. To achieve this goal, the following three questions will be addressed. (1) What is the molecular mechanism by which TDE0362 impairs host neutrophil and complement activation? (2) How does TDE0471 utilize host sialic acids to protect Td from complement killing? (3) How does glycosylation alter the innate immune response to Td flagellins? Completion of these studies will not only provide new insights into understanding the pathogenicity of Td at the molecular level, but also advance our current understanding of the uniqueness and complexity of periodontitis. One of the unique aspects about keystone pathogens is that while they trigger robust and hostile inflammation, they have also evolved complex mechanisms to evade host immune defenses, which allow them to thrive in the pocket, change symbiotic microbiota to dysbiosis, and cause tissue damage. Understanding their uniqueness and the underlying mechanisms will lead to new strategies to treat and prevent periodontitis.