Impact of Saccharibacteria and their bacterial hosts in Periodontal and Inflammatory Diseases

糖杆菌及其细菌宿主对牙周病和炎症性疾病的影响

• 批准号: 10541194
• 负责人: Batbileg Bor
• 金额: $ 52.18万
• 依托单位: ADA FORSYTH INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10541194
• 关键词: Actinobacteria class; Actinomyces; Address; Animal Model; Bacteria; Behavior; Biological Assay; Biological Process; Cell Communication; Cell Size; Cell Survival; Cells; Characteristics; Classification; Collaborations; Communities; Cultured Cells; Data; Development; Disease; Epithelial Cells; Epithelium; Eukaryotic Cell; Exposure to; Funding; Gene Expression Profile; Genes; Genetic; Genome; Gingiva; Grant; Health; Human; Immune; Immune response; Immunologics; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Investigation; Knowledge; Laboratories; Libraries; Life Style; Ligature; Link; Macrophage; Measures; Methods; Modeling; Mucous Membrane; Mus; Oral; Oral cavity; Pathogenesis; Pathogenicity; Patients; Periodontal Diseases; Periodontitis; Phagocytosis; Play; Radiation; Regulation; Research; Role; Site-Directed Mutagenesis; Surface; System; Taxonomy; Testing; Virulence Factors; bacterial genetics; chronic inflammatory disease; cytokine; design; dysbiosis; improved; in vivo; inflammatory bone loss; macromolecule; member; metatranscriptomics; mouse model; neutrophil; next generation sequencing; novel; opportunistic pathogen; oral microbiome; pathobiont; pathogenic bacteria; polymicrobial disease; response; tool; transcriptome; virulence gene

Abstract Human oral polymicrobial communities play a significant role in health and disease. Periodontitis is a polymicrobial disease and is among the most common infections of humans. Recent next-generation sequencing studies reveal that periodontal polymicrobial communities are comprised of a large diversity of bacterial species; however, we have little to no understanding of the disease-role of some of the key members. Saccharibacteria (TM7) is one such bacterial group that has been linked to multiple inflammatory diseases, including periodontitis. In addition, TM7 belongs to a major bacterial lineage termed Candidate Phyla Radiation. Candidate Phyla Radiation encompasses one-quarter of all bacterial diversity, yet they have been recalcitrant to laboratory cultivation. Oral TM7 bacteria were the first to be cultivated, opening the door to many intriguing questions due to their unique characteristics. TM7 has an ultra-small cell size (200-500 nm) with a highly reduced genome lacking essential biological functions. More importantly, it is an epiparasitic bacteria that grows on the surface of Actinobacteria (i.e., Actinomyces, Pseudopropionibacterium), which is another understudied bacterial group in humans. Actinomyces has been shown to induce inflammatory response both in cultured cells and in animal models. Our preliminary mouse periodontal studies were designed to investigate the role of TM7 and its host bacteria, Actinomyces, in vivo. TM7/host bacteria pairs induced less inflammatory bone loss compared to host bacteria alone, suggesting that oral Actinomyces and related bacteria can be a pathobiont (opportunistic pathogen), and their pathogenicity is regulated by TM7 bacteria. The current proposal will investigate pathogenic genes in TM7 host bacteria and how they are regulated by TM7 bacteria via metatranscriptomics. Identified genes will be further tested by site-directed mutagenesis in the host bacteria (Aim 1). The proposal will also determine the pathogenic and immunostimulatory activity of TM7 bacteria in epithelial and immune cell interaction assay and will identify TM7 macromolecules that are involved in their interaction with the eukaryotic cells (Aim 2). Lastly, this study will expand to culturing and characterizing additional taxonomically diverse TM7 bacteria from the periodontal patients, effectively creating a library of TM7 bacteria. This will allow us to determine the general immunological behavior of TM7/host bacteria across different TM7 species (Aim 3). Accomplishment of the proposal aims will improve the currently limited understanding of TM7 bacteria and its interaction with the host bacteria, as well as generate the first understanding of TM7's role in periodontal and inflammatory diseases.

抽象的 人类口腔多微生物群落在健康和疾病中发挥着重要作用。牙周炎是一种 多种微生物疾病，是人类最常见的感染之一。最近的下一代测序 研究表明，牙周多微生物群落由多种细菌物种组成； 然而，我们对一些关键成员的疾病作用知之甚少。糖细菌 (TM7) 就是这样一种细菌群，它与包括牙周炎在内的多种炎症性疾病有关。 此外，TM7 属于称为候选辐射门的主要细菌谱系。候选门 辐射涵盖了所有细菌多样性的四分之一，但它们一直难以实验室 栽培。口腔 TM7 细菌是第一个被培养出来的，这为许多有趣的问题打开了大门 到他们独特的特点。 TM7 具有超小细胞尺寸（200-500 nm）和高度缩减的基因组 缺乏必要的生物学功能。更重要的是，它是一种生长在物体表面的表寄生细菌。 放线菌（即放线菌属、假丙酸杆菌属）是另一个尚未得到充分研究的细菌群 人类。放线菌已被证明可以在培养细胞和动物中诱导炎症反应 模型。我们的初步小鼠牙周研究旨在研究 TM7 及其宿主的作用 细菌，放线菌，体内。与宿主相比，TM7/宿主细菌对引起的炎性骨质流失较少 单独的细菌，表明口腔放线菌和相关细菌可能是一种致病生物（机会性 病原体），其致病性受TM7细菌调节。目前的提案将调查致病性 TM7 宿主细菌中的基因以及它们如何通过宏转录组学受到 TM7 细菌的调节。已鉴定 将通过宿主细菌中的定点诱变进一步测试基因（目标 1）。该提案还将 确定TM7细菌在上皮细胞和免疫细胞中的致病活性和免疫刺激活性 相互作用测定，并将鉴定参与其与真核生物相互作用的 TM7 大分子 细胞（目标 2）。最后，这项研究将扩展到培养和表征其他分类学上多样化的 TM7 来自牙周患者的细菌，有效地创建了 TM7 细菌库。这将使我们能够确定 TM7/宿主细菌在不同 TM7 物种中的一般免疫学行为（目标 3）。成就 该提案的目的将提高目前对 TM7 细菌及其与细菌相互作用的有限了解。 宿主细菌，以及首次了解 TM7 在牙周和炎症疾病中的作用。