Immune regulation of the transcriptional and spatial profile of Clostridioides difficile

艰难梭菌转录和空间谱的免疫调节

• 批准号: 10448396
• 负责人: Michael C. Abt
• 金额: $ 20.31万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-09 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448396
• 关键词: Acute; Anatomy; Animals; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Infections; Biological Process; Biology; Cells; Clinic; Clinical; Clostridium difficile; Data; Data Set; Defense Mechanisms; Development; Diarrhea; Disease; Disease Outcome; Drug Metabolic Detoxication; Enteral; Epithelial; Exhibits; Fluorescent in Situ Hybridization; Foundations; Funding Mechanisms; Gastrointestinal tract structure; Gene Expression Profile; Genes; Genetic Transcription; Geographic Locations; Immune; Immune Evasion; Immune response; Immune system; Immunity; Immunodeficient Mouse; Immunofluorescence Microscopy; Immunologic Deficiency Syndromes; Immunologic Factors; Immunologics; Immunotherapy; Infection; Inflammation; Inflammatory Response; Interleukin-10; Intervention; Intestines; Lymphoid Cell; Mediating; Metabolic; Metabolism; Mucosal Immune System; Mucous Membrane; Mucous body substance; Mus; Nosocomial Infections; Nutrient; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Prevention; Production; RNA; Recurrence; Reporting; Reproduction spores; Research; Resources; Role; Severities; Severity of illness; Shapes; Tissues; Toxin; Transcriptional Regulation; Treatment Protocols; United States; Virulence; Virulence Factors; alternative treatment; antimicrobial; base; enteric pathogen; gut microbiome; high risk; immunological status; immunomodulatory therapies; immunoregulation; in vivo; insight; intestinal crypt; intestinal epithelium; metabolomics; microbiota; novel; novel strategies; opportunistic pathogen; pathogen; pressure; repaired; therapeutic target; transcriptome; transcriptomics; transmission process; treatment strategy; uptake

Project Summary Clostridiodies difficile is an opportunistic pathogen that can colonize a patient’s gastrointestinal tract following antibiotic perturbation of the intestinal microbiome. The quality of the host immune response to infection is an important factor in determining disease outcome. Immunodeficiencies leave the host acutely susceptible to infection, while unregulated host inflammation can drive disease (28). Interestingly, numerous clinical and animal studies have found the host immune response limits C. difficile-mediated tissue damage but does not directly drive pathogen clearance (4-12). However, the potential for host immune factors to shape C. difficile biology beyond total pathogen burden remains largely undefined. Previous studies have demonstrated that the biogeography and transcriptional activity of other pathogenic intestinal bacteria within the intestinal tract can be shaped by the mucosal immune system (13-16). Whether immunologic pressures shape C. difficile spatial and transcriptional profile has not been explored. This proposal utilizes distinct immunodeficient mice previously reported to exhibit a spectrum from mild to severe disease upon C. difficile infection despite indistinguishable C. difficile burden or toxin production. The aims of this proposal will first, visualize and quantify the C. difficile vegetative and spore burden in the mucus layer compared to the central lumen of the intestine under distinct immunologic conditions. Second, in complementary studies, the in vivo transcriptional profile of C. difficile will be assessed in mice harboring distinct immunologic deficiencies. Transcriptional pathways that promote sporulation, virulence factors, nutrient uptake, antimicrobial detoxification, and metabolic activity will be examined to understand how C. difficile responds to immune pressure to promote persistence and transmission. These aims will reveal novel immune-C. difficile interactions that determine disease severity and provide a template for how the immune response can be modulated to support conventional antibiotic treatment in treating C. difficile associated disease. 1

项目摘要 艰难梭菌是一种机会致病菌，可在感染后定植于患者的胃肠道。 抗生素干扰肠道微生物组。宿主对感染的免疫反应的质量是一个重要因素。 决定疾病结果的重要因素。免疫缺陷使宿主极易受到 感染，而不受调节的宿主炎症可以驱动疾病（28）。有趣的是，许多临床和 动物研究发现宿主免疫反应限制C.艰难介导的组织损伤，但不 直接驱动病原体清除（4-12）。然而，宿主免疫因素对C.艰难 总病原体负担之外的生物学仍然在很大程度上不确定。以前的研究表明， 可以通过免疫组织化学方法检测肠道内其他致病性肠道细菌的免疫组织化学和转录活性。 由粘膜免疫系统形成（13-16）。免疫压力是否形成C。难辨空间 和转录谱尚未被探索。该提议利用不同的免疫缺陷小鼠 先前报道的C.艰难感染，尽管 不可区分C。艰难梭菌负担或毒素产生。本提案的目的首先是形象化， 量化C.艰难梭菌营养体和孢子负荷的粘液层相比，中央腔的 肠道在不同的免疫条件下。第二，在补充研究中， C.将在具有明显免疫缺陷的小鼠中评估艰难梭菌。转录 促进孢子形成、毒力因子、营养吸收、抗菌解毒的途径，以及 代谢活动将被检查，以了解如何C。艰难梭菌对免疫压力的反应， 持久性和传输。这些目标将揭示新的免疫C。艰难的相互作用决定了 疾病的严重程度，并提供了一个模板，如何免疫反应可以调节，以支持 常规抗生素治疗C.艰难梭菌相关疾病 1