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