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）是第一道防线 防御微生物感染。在口腔中，先天免疫系统高度活跃， 维持口腔微生物群处于共生阶段。作为一种重要的病原体，口腔细菌 齿垢密螺旋体（Td）具有高度运动性和侵袭性， 龈下菌斑，在那里它直接面对宿主的免疫反应。TD能够侵入主机 免疫防御，生存，甚至成为主导牙周袋时， 生态失调和炎症（例如，严重和难治性牙周炎）。底层 使Td逃避宿主免疫反应的机制仍然很大程度上未知。期间 在上一个资助周期，我们在Td中发现了几个新的毒力因子。其中，我们 发现TDE 0362（一种半胱氨酸蛋白酶）和TDE 0471（一种唾液酸酶）具有独特的生物化学特性， 结构特征，保护Td免受补体和中性粒细胞的杀伤，并在免疫系统中发挥关键作用。 致病性我们还鉴定了一种修饰Td鞭毛蛋白的新型聚糖， 这种独特的修饰不仅对Td的鞭毛形成和运动性至关重要， 对鞭毛蛋白的先天免疫反应在这些调查结果的基础上，这次更新的目的是 阐明这三个新的致病性状的TD的分子机制。到 为了实现这一目标，将处理以下三个具体问题。(1)什么是分子 TDE 0362损害宿主中性粒细胞和补体激活的机制？(2)如何 TDE 0471利用宿主唾液酸保护Td免受补体杀伤？(3)糖基化是如何 改变对Td鞭毛蛋白的先天免疫反应解决这些问题不仅可以提供 在分子水平上理解Td的致病性的新见解，也推进了我们的研究。 目前对牙周炎的独特性和复杂性的认识。一个独特的方面是 关于关键病原体的一点是，虽然它们会引发强烈的和敌对的炎症， 还进化出复杂的机制来逃避宿主的免疫防御，这使得它们能够在宿主体内茁壮成长。 口腔，将共生微生物群改变为生态失调，并导致组织损伤。在这方面，委员会注意到， 了解它们的独特性和潜在机制将导致新的治疗策略， 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.