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

• 批准号: 10314304
• 负责人: Mary Ellen Davey
• 金额: $ 58.54万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 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/10314304
• 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; Mediating; Membrane; Metabolism; Methodology; Methods; Microbe; Modeling; Molecular; Mucous Membrane; Mus; Nature; Oral; 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; macrophage; 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

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.

项目摘要 真核SLS是细胞膜的基本构建基块，并用作关键信号分子。 SLS的细菌合成知之甚少，几乎完全仅限于菌植物。 这些微生物通常被认为是哺乳动物宿主的符号。虽然微生物引起的慢性 注射失调是软组织破坏和牙周疾病的核心特征 发病机理，这种炎症是矛盾的，不足以清除感染的来源。那，颠覆 宿主的免疫力是该疾病慢性性质的核心。研究表明卟啉念珠菌 牙龈牙龈，细菌植物的成员具有靶向和动态免疫抑制的独特能力， 然而，对基本机制知之甚少。值得注意的是，我们的研究阐明了 牙龈疟原虫在确定引起的宿主对该生物的免疫反应时，我们表明 这些SLS从该生物体转移并掺入宿主细胞中 - 概括地理解为 Interkingdom通信系统。我们提出的研究的总体假设是合成 SLS提供牙龈疟原虫和可能的其他口服杀菌剂一种免疫调节的机制。 具体而言，我们已发表的初步研究确定牙龈疟原虫分泌含Sl的SL 与牙龈疟原虫相比，仅引起轻度炎症的外膜蔬菜（OMV） 突变体无法合成SLS，并且磷酸甘油二氢酰亚胺（SLS的子集） 含有OMV特别擅长免疫抑制。我们建议SL-OMV是一个 精致的交付系统构成了牙龈疟原虫托管机制的基础 炎。我们拟议的研究的目的是确定牙龈疟原虫SLS如何有助于OMV货物 这些SL-OMV如何调节宿主先天炎症反应。我们将 在体外和体内对牙龈疟原虫sl-omvs的询问宿主传感。作为早期先天免疫反应 在粘膜表面（例如口腔）的控制宿主反应，我们将采用独特的基因修饰 牙龈疟原虫菌株和从这些菌株中分离出的OMV，以确定涉及哪些OMV组件 在抑制中。分子，免疫学，成像和转录组和生化技术将是 部署以阐明SL-OMV的基本功能和主机先天信号的机制。最后， 我们将使用口腔损失模型检查牙龈疟原虫菌株的病毒，这些病毒在 SLS的合成。这些研究的基本原理是，确定使用的免疫调节机制 口腔病原体将为理论策略的发展提供主要目标。那，长期 该研究计划的目标是阐明SL介导的OMV的基础机制已交付的免疫 抑制并确定是否可以针对细菌SL合成来治疗和预防 牙周疾病。