Exploring new virulence factors of the oral spirochete Treponema denticola

先天免疫系统(即补体和中性粒细胞介导的杀伤)是 防御微生物感染。在口腔中，先天免疫系统高度活跃， 维持口腔微生物区系处于共生阶段。作为一种关键病原体，口腔细菌 齿密螺旋体(Td)具有高度的运动性和侵袭性，处于 牙龈下菌斑，在那里它直接对抗宿主的免疫反应。TD能够攻破主机 免疫防御，存活，甚至在牙周袋中占主导地位 生物失调和炎症恶化(例如，在严重和难治性牙周炎中)。潜在的 TD逃避宿主免疫反应的机制在很大程度上仍不清楚。在.期间 在上一个资金周期，我们在TD中发现了几个新的毒力因子。在这些因素中，我们 发现TDE0362(一种半胱氨酸蛋白酶)和TDE0471(一种唾液酸酶)具有独特的生化和 结构特征，保护TD免受补体和中性粒细胞的杀伤，并在 TD的致病性。我们还鉴定了一种新的修饰TD鞭毛蛋白的多糖，并发现 这一独特的修饰不仅对TD的鞭毛和运动至关重要，而且还改变了TD 对鞭毛的先天免疫反应。在这些调查结果的基础上，此次更新旨在 阐明TD的这三个新的致病特性背后的分子机制。至 要实现这一目标，将解决以下三个具体问题。(1)分子是什么 TDE0362损害宿主中性粒细胞和补体激活的机制？(2)如何 TDE0471利用宿主唾液酸保护TD免受补体杀伤？(3)糖基化是如何 改变TD鞭毛蛋白的先天免疫反应？解决这些问题不仅会提供 在分子水平上理解TD的致病性的新见解，也促进了我们的 目前对牙周炎的独特性和复杂性的认识。其中一个独特的方面 关于Keystone病原体的是，尽管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 口腔，使共生微生物群变得生态各异，造成组织损伤。在这方面， 了解它们的独特性和潜在机制将导致新的治疗和治疗策略 预防牙周炎。

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 motile and 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 periodontal 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 found that 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 specific 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? Addressing these questions 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 the 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 oral cavity, change symbiotic microbiota to dysbiosis, and cause tissue damage. In this regard, understanding their uniqueness and underlying mechanisms will lead to new strategies to treat and prevent periodontitis.