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.

项目摘要 本申请的总体目标是更好地理解和利用第3组先天淋巴细胞（ILC 3）生物学 以增强对艰难梭菌感染（CDI）的粘膜免疫应答。我们缺乏有效的 这种病原体的治疗，迫切需要更好地了解C. difficile与我们的 免疫系统ILC 3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C.很难在活化后，ILC 3分泌高水平的细胞因子白细胞介素-22（IL-22） 其是炎症期间组织反应的关键调节剂。我们最近发表的研究表明， 主要毒力因子C.艰难梭菌毒素B（TcdB）直接激活ILC 3。此外，其他人的工作 显示施用重组IL-22在小鼠CDI模型中提供保护，表明 在感染期间将细胞因子提高到其自然产生的水平可以帮助CDI患者。所以我们 正在研究ILC 3中对激活重要的分子途径，以确定新的途径来增强 功能一个非常感兴趣的途径家族是细胞代谢。初步数据显示， 多胺正调节TcdB介导的ILC 3活化。多胺水平增加， ILC 3s，并且当关键生物合成酶被抑制时，ILC 3s产生较少的IL-22。多胺很重要 在转录和翻译中，在其他免疫细胞的活化中具有重要作用， 在ILC 3中进行了研究。中心假设是多胺生物学对于ILC 3活化是重要的， 多胺可用于改善C.难治性感染和/或复发。本提案中 我们将研究代谢途径如何控制ILC 3激活，这对这些疾病有着可翻译的意义。 免疫细胞C.艰难感染中心假设将通过追求两个具体目标进行测试：1） 确定了C.艰难梭激活的ILC 3和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，我们将采取有针对性的措施， 非靶向方法来确定多胺在C.艰难梭介导的ILC 3 activation.第二个目标将测试多胺如何在体内靶向增强先天免疫反应 从而预防或降低原发性或复发性疾病的CDI严重程度。在完成这些目标后， 预期的结果是双重的，因为我们将（1）获得基本免疫学的理解， 多胺调节ILC 3的激活和（2）确定多胺如何被转化的可能性。 在CDI期间使用以增强免疫力。这些结果将对我们理解 免疫反应C.困难，因为它们将为进一步开发 CDI患者的ILC 3和IL-22生物靶向治疗。