Microbial sphingolipids and suppression of host inflammation in periodontal disease

微生物鞘脂和牙周病宿主炎症的抑制

基本信息

批准号：
10640238
负责人：
Mary Ellen Davey
金额：
$ 58.16万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640238
关键词：
Affect Atmosphere Bacteroides Bacteroidetes Biochemical Cell Communication Cell Culture Techniques Cell membrane Cells Chemistry Chronic Clinical Collaborations Communication Development Disease Elements Genes Genetic Genetic Transcription Gingiva Goals Growth Health Human Image Immune Immune response Immunity Immunologics Immunosuppression In Vitro Infection Inflammation Inflammatory Response Innate Immune Response Knowledge Lipids Macrophage Mediating Membrane Metabolism Methodology Methods Microbe Modeling Molecular Mucous Membrane Mus Nature Oral Oral Examination Oral cavity Organism Pathogenesis Pathogenicity Periodontal Diseases Physiology Play Porphyromonas gingivalis Prevention Prokaryotic Cells Proteins Publications Publishing Research Role Signal Pathway Signal Transduction Signaling Molecule Source Sphingolipids Surface System Techniques Testing Tissues Tooth structure Vesicle Virulence Vision bone loss cell motility cytokine defined contribution immune function immunoregulation in vivo inflammatory milieu intestinal homeostasis member microbial microscopic imaging mutant neutrophil novel oral infection oral pathogen periodontopathogen programs response subgingival microbiota symbiont targeted treatment therapeutic development trafficking transcriptome sequencing transcriptomics treatment strategy

项目摘要

PROJECT SUMMARY Eukaryotic SLs are the basic building blocks of cell membranes and serve as key signaling molecules. Bacterial synthesis of SLs is poorly understood, and almost entirely restricted to the phylum Bacteroidetes. These microbes are generally considered symbionts of mammalian hosts. Although microbe-elicited chronic dysregulated inflammation is central feature of soft and hard tissue destruction and periodontal disease pathogenesis, this inflammation is, paradoxically, insufficient to clear the source of infection. Thus, subversion of host immunity is central to the chronic nature of this disease. Research has shown that Porphyromonas gingivalis, a member of the Bacteroidetes is uniquely capable of targeted and dynamic immune suppression, yet little is known of the underlying mechanisms. Remarkably, our studies have illuminated the importance of P. gingivalis SL in regulating the elicited host immune response to this organism and we have shown that these SLs are transferred from this organism and incorporated into host cells – putatively understood as an interkingdom communication system. The overarching hypothesis of the research we propose is that synthesis of SLs affords P. gingivalis and possibly other oral Bacteroidetes a mechanism of immune regulation. Specifically, our published and preliminary studies have determined that P. gingivalis secretes SL-containing outer membrane vesicles (OMVs) that elicit only mild inflammation compared to OMVs from a P. gingivalis mutant incapable of synthesizing SLs, and that the phosphoglycerol-dihydrocerimides (a subset of SLs) containing OMVs are particularly adept at immune suppression. We are proposing that SL-OMVs are an exquisite delivery system that forms the basis of a mechanism of P. gingivalis-host communication to control inflammation. The goal of our proposed studies is to determine how P. gingivalis SLs contribute to OMV cargo loading and subsequently how these SL-OMVs modulate the host innate inflammatory response. We will interrogate host sensing of P. gingivalis SL-OMVs both in vitro and in vivo. As early innate immune responses control host responses at mucosal surfaces such as the oral cavity, we will employ unique genetically modified P. gingivalis strains, and OMVs isolated from these strains to determine which OMV-components are involved in suppression. Molecular, immunologic, imaging, and transcriptomic, and biochemical techniques will be deployed to elucidate the underlying functions of SL-OMVs and mechanisms of host innate signaling. Lastly, we will use oral bone loss modelling to examine the virulence of P. gingivalis strains that are altered in the synthesis of SLs. The rationale for these studies is that identifying immunoregulatory mechanisms used by oral pathogens will provide prime targets for the development of therapeutic strategies. Thus, the long-term goal of this research program is to elucidate the mechanisms underlying SL-mediated OMV delivered immune suppression and to determine if bacterial SL-synthesis can be targeted for treatment and prevention of periodontal disease.

项目概要真核细胞 SL 是细胞膜的基本组成部分，是关键的信号分子。人们对 SL 的细菌合成知之甚少，并且几乎完全局限于拟杆菌门。这些微生物通常被认为是哺乳动物宿主的共生体，尽管微生物引起的慢性。炎症失调是软组织和硬组织破坏和牙周病的核心特征矛盾的是，这种炎症不足以清除感染源，从而颠覆。研究表明，宿主免疫力的下降是这种疾病的慢性本质的核心。牙龈杆菌是拟杆菌门的一员，具有独特的靶向和动态免疫抑制能力，但我们对潜在机制知之甚少，值得注意的是，我们的研究已经阐明了其重要性。 P. gingivalis SL 调节宿主对该生物体的免疫反应，我们已经证明这些 SL 从该生物体转移并整合到宿主细胞中 – 假定被理解为我们提出的研究的总体假设是综合。 SL 为牙龈卟啉单胞菌和可能的其他口腔拟杆菌提供了免疫调节机制。具体来说，我们已发表的初步研究已确定牙龈卟啉单胞菌分泌含有 SL 的物质与牙龈卟啉单胞菌的外膜囊泡 (OMV) 相比，仅引起轻度炎症突变体无法合成 SL，并且磷酸甘油二氢神经酰胺（SL 的一个子集）含有 OMV 的药物特别擅长免疫抑制。我们建议 SL-OMV 是一种免疫抑制药物。精致的传递系统，形成牙龈卟啉单胞菌-宿主通讯控制机制的基础我们提出的研究的目标是确定牙龈卟啉单胞菌 SL 如何促进 OMV 运输。我们将了解这些 SL-OMV 的负载以及随后如何调节宿主先天炎症反应。在体外和体内询问宿主对牙龈卟啉单胞菌 SL-OMV 的感知作为早期先天免疫反应。控制粘膜表面（例如口腔）的宿主反应，我们将采用独特的转基因技术牙龈卟啉单胞菌菌株，以及从这些菌株中分离出的 OMV，以确定涉及哪些 OMV 成分分子、免疫学、成像、转录组学和生化技术将受到抑制。部署用于阐明 SL-OMV 的基本功能和宿主固有信号传导机制。我们将使用口腔骨质流失模型来检查在口腔中发生改变的牙龈卟啉单胞菌菌株的毒力这些研究的基本原理是确定 SL 的合成。因此，口腔病原体将为制定长期治疗策略提供主要目标。该研究计划的目标是阐明 SL 介导的 OMV 传递免疫的潜在机制抑制并确定细菌 SL 合成是否可以作为治疗和预防的目标牙周病。