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: 10344399
• 负责人: Batbileg Bor
• 金额: $ 55.79万
• 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/10344399
• 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; Epithelial Cells; 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; 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; base; chronic inflammatory disease; cytokine; design; dysbiosis; improved; in vivo; inflammatory bone loss; macromolecule; macrophage; member; metatranscriptomics; mouse model; neutrophil; next generation sequencing; novel; opportunistic pathogen; oral microbiome; pathobiont; pathogenic bacteria; polymicrobial disease; response; tool; transcriptome

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 人口腔多生物群落在健康和疾病中起着重要作用。牙周炎是 多数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，牙周多生物群落由大量细菌种类组成。 但是，我们对某些主要成员的疾病角色几乎没有理解。糖精 （TM7）是一个与多种炎症性疾病有关的细菌组，包括牙周炎。 另外，TM7属于一个主要的细菌谱系称为候选门辐射。候选门 辐射包括所有细菌多样性的四分之一，但它们一直是实验室 耕种。口服TM7细菌是第一个培养的细菌，为许多有趣的问题打开了大门 具有其独特的特征。 TM7具有高度降低的基因组的超小细胞大小（200-500 nm） 缺乏基本的生物学功能。更重要的是，这是一种表面上生长的表面性细菌 放线菌（即放线菌，伪丙二离子杆菌），这是另一个研究的细菌群 人类。放线肌已显示出在培养细胞和动物中诱导炎症反应 型号。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 仅细菌，表明口服放线菌和相关细菌可以是病原体（机会性 病原体），其致病性受TM7细菌调节。当前的建议将研究致病性 TM7宿主细菌中的基因及其如何通过元文字组学调节TM7细菌。确定 基因将通过宿主细菌中定位的诱变进一步测试（AIM 1）。该提议也将 确定TM7细菌在上皮和免疫细胞中的致病性和免疫刺激活性 相互作用测定，将识别与真核互动涉及的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不同的TM7 牙周患者的细菌有效地创建了TM7细菌的库。这将使我们确定 TM7/宿主细菌在不同TM7种类中的一般免疫学行为（AIM 3）。成就 该提案的目的将改善当前对TM7细菌的了解及其与该细菌的相互作用 宿主细菌，并首先了解TM7在牙周和炎症性疾病中的作用。