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

项目总结/摘要 研究：牙周炎（牙龈疾病）是世界上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）。未经治疗，它可以破坏组织， 支持牙齿，最终导致牙齿脱落。牙周炎的病因与牙周组织的生长有关。 口腔微生物群中的多种病原体，而不是单个病原体。例如，联合检测聚集杆菌 放线菌伴放线菌（Aa）与Filifactoralocis是一个更大的预测未来的组织破坏比 单独检测Aa。然而，Aa和F. alocis相互作用以引起病理，同时逃避宿主免疫 仍然知之甚少。微生物-宿主相互作用通常由微生物代谢产物介导， 主要代谢产物F. Alocis是硫化氢，一种在牙周炎中高度富集的有毒气体。根据我 初步数据，我假设F。芦荟衍生的硫化物引发免疫级联反应， 破坏，同时构建一个小生境Aa增殖通过耐硫厌氧呼吸。值得注意的是， 已经存在选择性抑制厌氧呼吸（钨酸盐）或螯合的廉价无毒药物。 硫化物（铋）。为了验证我的假设和这些药物的治疗价值，我将解剖F。alocis- 衍生硫化物影响Aa（Aim 1）和补充小鼠模型中的口服免疫系统（Aim 2）：大腿 脓肿，这允许精确控制感染社区的组成， 牙周炎，这允许口腔免疫反应的评估。通过这些目标，我将有可能 建立针对促进牙周病的微生物-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医学领域， 微生物学和免疫学作为一种策略，以获得新的洞察牙周炎的病因。实现这一 我的目标是，我需要额外的培训和知识，在口腔免疫学以及专业发展的技能 这是一个成功的实验室的关键。职业发展规划与环境：我的导师Y。 Belkaid是微生物与宿主相互作用方面的著名专家， 该计划是世界上最大的研究中心之一。在这种独特的环境中，我将直接受益于 有许多资源支持我的研究项目和职业发展，包括微生物组 和免疫学核心设施，经常研讨会和机会，让同事/导师，并定期 关于资助申请、指导和实验室管理的研讨会。此外，我还收集了一个 指导团队将通过密切监督我在Aa和脓肿模型方面的专业知识， 在结扎模型中训练（基于NIDCR的合作者N. Moutsopoulos）和F. alocis（合作者R.拉蒙 和H.弗莱彻）以及我向独立的过渡。在我的训练计划结束时， 在口腔微生物学和免疫学的交叉点开展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.