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.

摘要 人类口腔微生物群落在健康和疾病中起着重要作用。牙周炎是一 多微生物疾病，是人类最常见的感染。最近的下一代测序 研究揭示牙周多微生物群落由多种多样的细菌物种组成; 然而，我们对一些关键成员的疾病作用几乎一无所知。酵母菌 (TM7)是一个这样的细菌群，它与包括牙周炎在内的多种炎症性疾病有关。 此外，TM 7属于一个主要的细菌谱系，称为候选门辐射。候选人Phyla 辐射包含了所有细菌多样性的四分之一，但它们一直没有被实验室检测到。 修为口腔TM 7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， 他们独特的特征。TM 7具有超小的细胞尺寸（200-500 nm），基因组高度简化 缺乏基本的生物功能。更重要的是，它是一种寄生在表面的细菌， 放线菌（即，放线菌，假丙酸杆菌），这是另一个未充分研究的细菌群， 人类放线菌已被证明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调查TM 7及其宿主的作用， 细菌，放线菌，在体内。与宿主相比，TM 7/宿主细菌对诱导较少的炎性骨丢失 单独的细菌，表明口腔放线菌和相关细菌可以是致病菌（机会性 病原菌），其致病性受TM 7细菌调控。目前的建议将调查致病性 TM 7宿主细菌中的基因以及它们如何通过元转录组学被TM 7细菌调控。识别 将通过在宿主细菌中的定点诱变进一步测试基因（Aim 1）。该提案还将 确定TM 7细菌在上皮细胞和免疫细胞中的致病性和免疫刺激活性 相互作用测定，并将鉴定参与其与真核生物相互作用的TM 7大分子 细胞（目标2）。最后，本研究将扩展到培养和表征其他分类学上不同的TM 7 从牙周病患者的细菌，有效地创建了一个图书馆的TM 7细菌。这将使我们能够确定 不同TM 7物种间TM 7/宿主细菌的一般免疫学行为（目的3）。成就 该提案的目的将改善目前对TM 7细菌及其与细菌相互作用的有限了解。 宿主细菌，以及产生的第一次了解TM 7的牙周和炎症性疾病的作用。