Understanding and leveraging immunometabolism to combat Clostridioides difficile infection

了解并利用免疫代谢来对抗艰难梭菌感染

• 批准号: 10750341
• 负责人: Lauren A Zenewicz
• 金额: $ 53.1万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750341
• 关键词: Affect; Amino Acids; Arginine; Autoimmunity; Bacteria; Bacterial Infections; Biology; Cell physiology; Cells; Clostridium difficile; DL-alpha-Difluoromethylornithine; Data; Development; Disease; Elderly; Enzymes; Epithelium; FDA approved; Failure; Family; Gastrointestinal tract structure; Gene Expression Regulation; Genetic Transcription; Glycolysis; Goals; Health; Immune; Immune response; Immune system; Immunity; Immunocompromised Host; Immunology; Incidence; Infection; Inflammation; Innate Immune Response; Intoxication; Ion Transport; Lymphocyte; Lymphocyte Activation; Lymphocyte Biology; Malignant Neoplasms; Mediating; Metabolic Pathway; Metabolism; Mission; Modeling; Molecular; Morbidity - disease rate; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Natural Immunity; Ornithine Decarboxylase; Outcome; Oxidative Phosphorylation; Pathway interactions; Patients; Pharmaceutical Preparations; Polyamines; Primary Infection; Production; Proliferating; Protein Analysis; Protein Biosynthesis; Public Health; Publishing; Putrescine; Recombinant Interleukins; Recurrence; Recurrent disease; Relapse; Research; Role; Severities; Severity of illness; Spermidine; Spermine; Testing; Tissues; Toxin; Translations; United States National Institutes of Health; Vaccines; Virulence Factors; Work; combat; cytokine; effective therapy; enzyme biosynthesis; evidence base; gastrointestinal; gastrointestinal infection; human disease; improved; improved outcome; in vivo; interest; interleukin-22; interleukin-23; mortality; novel; pathogen; pathogenic bacteria; phase III trial; prevent; response; secondary infection; targeted treatment; transcriptome sequencing

PROJECT SUMMARY The overall goal of this application is to better understand and harness group 3 innate lymphocyte (ILC3) biology to enhance mucosal immune responses to Clostridioides difficile infection (CDI). We lack fully effective treatments for this pathogen and there is critical need to better understand how C. difficile interacts with our immune system. ILC3s are rare immune cells localized within mucosal tissues that help protect against bacterial infections, including C. difficile. Upon activation, ILC3s secrete high levels of the cytokine interleukin-22 (IL-22) which is a critical regulator of tissue responses during inflammation. Our recent published study shows that a major virulence factor of C. difficile, toxin B (TcdB), directly activates ILC3s. Furthermore, work from others has shown that administration of recombinant IL-22 provides protection in a mouse CDI model suggesting that boosting the cytokine over its naturally produced levels during infection could aid CDI patients. Therefore, we are investigating the molecular pathways in ILC3s important for activation to identify novel pathways to enhance function. One family of pathways of great interest is cellular metabolism. Our preliminary data show that polyamines positively regulate TcdB-mediated activation of ILC3s. Polyamine levels are increased in activated ILC3s and when the key biosynthesis enzyme is inhibited, ILC3s produce less IL-22. Polyamines are important in transcription and translation, have important roles in activation of other immune cells and have yet to be fully investigated in ILC3s. The central hypothesis is that polyamine biology is important for ILC3 activation, and polyamines can be leveraged for improving outcomes to C. difficile infection and/or recurrence. In this proposal we will examine how a metabolic pathway controls ILC3 activation, which has translatable implications on these immune cells in C. difficile infection. The central hypothesis will be tested by pursuing two specific aims: 1) Determine the mechanism(s) of polyamine function in C. difficile-activated ILC3s and 2) Determine how to leverage polyamine biology in primary and recurrent CDI. Under the first aim, we will undertake targeted and untargeted approaches to determine the cellular pathway(s) that polyamines target in C. difficile-mediated ILC3 activation. The second aim will test how polyamines can be targeted in vivo to boost the innate immune response and thereby prevent or reduce CDI severity in primary or recurrent disease. Upon completion of these aims, the expected outcomes are two-fold as we will (1) gain an understanding of fundamental immunology of how polyamines regulate ILC3 activation and (2) determine the translatable potential of how polyamines can be leveraged during CDI to boost immunity. These results will have a positive impact on our understanding of immune responses to C. difficile as they will provide strong evidence-based rationale for further development of ILC3 and IL-22 biology targeted therapies for CDI patients.

项目概要 此应用程序的总体目标是更好地了解和利用第 3 组先天淋巴细胞 (ILC3) 生物学 增强对艰难梭菌感染（CDI）的粘膜免疫反应。我们缺乏完全有效的 针对这种病原体的治疗方法，迫切需要更好地了解艰难梭菌如何与我们的相互作用 免疫系统。 ILC3 是位于粘膜组织内的罕见免疫细胞，有助于防止细菌感染 感染，包括艰难梭菌。激活后，ILC3 会分泌高水平的细胞因子白细胞介素 22 (IL-22) 它是炎症期间组织反应的关键调节因子。我们最近发表的研究表明 艰难梭菌的主要毒力因子毒素 B (TcdB) 直接激活 ILC3。此外，其他人的工作 表明重组 IL-22 的施用在小鼠 CDI 模型中提供了保护，这表明 在感染期间提高细胞因子的自然产生水平可能会对 CDI 患者有所帮助。因此，我们 正在研究 ILC3 中对于激活很重要的分子途径，以确定增强的新途径 功能。细胞代谢是一系列令人感兴趣的途径。我们的初步数据表明 多胺正向调节 TcdB 介导的 ILC3 激活。活性物质中的多胺水平增加 ILC3，当关键生物合成酶受到抑制时，ILC3 产生的 IL-22 会减少。多胺很重要 在转录和翻译中，在其他免疫细胞的激活中具有重要作用，但尚未得到充分研究 在 ILC3 中进行了研究。中心假设是多胺生物学对于 ILC3 激活很重要，并且 多胺可用于改善艰难梭菌感染和/或复发的结果。在这个提案中 我们将研究代谢途径如何控制 ILC3 激活，这对这些具有可转化的影响 艰难梭菌感染中的免疫细胞。将通过追求两个具体目标来检验中心假设：1） 确定艰难梭菌激活的 ILC3 中多胺功能的机制，以及 2) 确定如何 在原发性和复发性 CDI 中利用多胺生物学。在第一个目标下，我们将有针对性地开展 确定多胺在艰难梭菌介导的 ILC3 中靶向的细胞途径的非靶向方法 激活。第二个目标将测试多胺如何在体内靶向以增强先天免疫反应 从而预防或减轻原发性疾病或复发性疾病的 CDI 严重程度。完成这些目标后， 预期结果是双重的，因为我们将（1）了解基本免疫学如何 多胺调节 ILC3 激活并 (2) 确定多胺如何转化的潜力 在 CDI 期间利用来增强免疫力。这些结果将对我们的理解产生积极的影响 对艰难梭菌的免疫反应，因为它们将为进一步发展提供强有力的基于证据的理论依据 CDI 患者的 ILC3 和 IL-22 生物靶向治疗。