Role of sulfide in oral microbiota-host interactions that promote periodontitis

项目摘要/摘要 研究：牙周炎(牙周病)是全球最常见的炎症性疾病之一， 仅在美国就影响了近50%的成年人(6500万人)。如果不治疗，它可能会破坏 支撑牙齿，最终导致牙齿脱落。牙周炎的原因与牙周炎的发生有关。 口腔微生物区系中的多个病原体，而不是单个病原体。例如，Aggregatibacter的联合检测 伴生放线菌(AA)和纤溶酶原激活剂(Filifactoralocis)对未来组织破坏的预测要比 单独检测AA。然而，AA和F.alocis是如何在逃避宿主免疫的同时相互作用来引发病理的 人们对此仍然知之甚少。微生物群与宿主的相互作用通常由微生物代谢物介导，而 白粉菌的主要代谢物是硫化氢，这是一种在牙周炎中高度浓缩的有毒气体。基于我的 初步数据显示，我推测金黄色葡萄球菌衍生的硫化物会引发免疫级联反应，从而驱动组织 破坏，同时为AA构建一个通过抗硫化物厌氧呼吸增殖的生态位。值得注意的是， 廉价、无毒的药物已经存在，可以选择性地抑制无氧呼吸(钨酸盐)或隔离。 硫化物(铋)。为了检验我的假设和这些药物的治疗价值，我将剖析阿洛克斯菌是如何-- 衍生的硫化物对AA(AIM 1)和口服免疫系统(AIM 2)的影响在互补小鼠模型中：大腿 脓肿，允许精确控制感染群落的组成，以及结扎诱导的 牙周炎，这允许评估口腔免疫反应。通过这些目标，我将有可能 建立针对促进牙周病的微生物群-宿主相互作用的创新疗法。 职业目标：作为一名独立调查员，我的首要目标是整合口腔领域 微生物学和免疫学作为一种策略，以获得对牙周炎病因的新见解。要做到这一点 我的目标是，我需要额外的口腔免疫学培训和知识，以及技能方面的专业发展 对于领导一个成功的实验室是必不可少的。职业发展计划与环境：我的导师Y。 贝尔凯德是微生物群-宿主相互作用方面的著名专家，也是美国国立卫生研究院内部研究中心的研究员 计划，世界上最大的研究中心之一。在这个独特的环境中，我将直接受益于 支持我的研究项目和职业发展的众多资源，包括微生物组 和免疫学核心设施，频繁的研讨会和接触同事/导师的机会，以及定期 关于赠款编写、指导和实验室管理的讲习班。此外，我还组装了一个 指导团队将补充我在AA和脓肿模型方面的专业知识，密切监督我的 结扎模型(基于NIDCR的共同导师N.Moutsopoulos)和F.alocis(合作者R.Lamont)的培训 和H·弗莱彻)以及我向独立的过渡。在我的训练计划结束时，我将处于有利地位 在口腔微生物学和免疫学的交叉点上开始富有成效的独立职业生涯。

Project Summary/Abstract Research: Periodontitis (gum disease) is one of the most common inflammatory diseases worldwide, affecting nearly 50% of adults (65 million people) in the US alone. Untreated, it can destroy the tissues that support the teeth, eventually resulting in tooth loss. The cause of periodontitis is linked to the outgrowth of multiple, rather than individual, pathogens in the oral microbiota. For instance, co-detection of Aggregatibacter actinomycetemcomitans (Aa) with Filifactor alocis is a much greater predictor of future tissue destruction than detection of Aa alone. However, how Aa and F. alocis interact to elicit pathology while evading host immunity remains poorly understood. Microbiota-host interactions are often mediated by microbial metabolites, and a major metabolite of F. alocis is hydrogen sulfide, a toxic gas highly enriched in periodontitis. Based on my preliminary data, I hypothesize that F. alocis-derived sulfide triggers an immunological cascade that drives tissue destruction while constructing a niche for Aa to proliferate via sulfide-resistant anaerobic respiration. Of note, inexpensive, non-toxic drugs already exist that selectively inhibit anaerobic respiration (tungstate) or sequester sulfide (bismuth). To test my hypothesis and the therapeutic value of these drugs, I will dissect how F. alocis- derived sulfide impacts Aa (Aim 1) and the oral immune system (Aim 2) in complementary mouse models: thigh abscess, which allows for precise control over composition of the infecting community, and ligature-induced periodontitis, which allows for the assessment of oral immune responses. Through these Aims, I will potentially establish innovative therapies targeted against microbiota-host interactions that promote periodontal disease. Career Goals: My overarching goal as an independent investigator is to integrate the fields of oral microbiology and immunology as a strategy to gain novel insight into the etiology of periodontitis. To achieve this goal, I require additional training and knowledge in oral immunology as well as professional development in skills essential for leading a successful laboratory. Career Development Plan and Environment: My mentor Y. Belkaid, a renowned expert in microbiota-host interactions, is an investigator in the NIH Intramural Research Program, one of the largest research centers in the world. In this unique environment, I will directly benefit from the numerous resources in place to support my research project and career development, including microbiome and immunology core facilities, frequent seminars and opportunities to engage colleagues/mentors, and regular workshops on grant-writing, mentoring, and laboratory management. Furthermore, I have assembled a mentoring team who will complement my expertise in Aa and the abscess model by closely overseeing my training in the ligature model (NIDCR-based co-mentor N. Moutsopoulos) and F. alocis (collaborators R. Lamont and H. Fletcher) as well as my transition to independence. By the end of my training plan, I will be well-positioned to launch a productive independent career at the intersection of oral microbiology and immunology.