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

项目概要 艰难梭菌是一种机会性病原体，可在患者胃肠道中定殖 抗生素对肠道微生物组的干扰 宿主对感染的免疫反应的质量是一个影响因素。 决定疾病结果的重要因素。 感染，而不受控制的宿主炎症会导致疾病 (28)。 动物研究发现宿主免疫反应限制了艰难梭菌介导的组织损伤，但并没有 直接驱动病原体清除 (4-12) 然而，宿主免疫因素有可能塑造艰难梭菌。 先前的研究表明，除了总病原体负荷之外的生物学仍然没有明确的定义。 肠道内其他致病性肠道细菌的生物地理学和转录活性可以 由粘膜免疫系统塑造 (13-16)。 并且尚未探索转录谱。该提案利用了不同的免疫缺陷小鼠。 此前有报道称，艰难梭菌感染后表现出从轻微到严重的疾病谱，尽管 难以区分艰难梭菌负荷或毒素产生 该提案的目的首先是可视化和可视化。 与粘液层中央腔相比，量化艰难梭菌营养体和孢子负荷 其次，在补充研究中，体内转录。 将在具有明显转录缺陷的小鼠中评估艰难梭菌的概况。 促进孢子形成、毒力因子、营养吸收、抗菌解毒和 将检查代谢活动，以了解艰难梭菌如何响应免疫压力以促进 这些目标将揭示决定艰难梭菌的新的免疫相互作用。 疾病严重程度并提供如何调节免疫反应以支持的模板 治疗艰难梭菌相关疾病的常规抗生素治疗。 1