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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要该应用的总体目标是更好地理解和利用3个先天淋巴细胞（ILC3）生物学为了增强对梭状芽胞杆菌艰难梭菌感染（CDI）的粘膜免疫反应。我们缺乏完全有效的对这种病原体的治疗，至关重要的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是罕见的免疫细胞，粘液组织中有助于预防细菌感染，包括艰难梭菌。激活后，ILC3分泌高水平的细胞因子白介素22（IL-22）这是炎症过程中组织反应的关键调节剂。我们最近发表的研究表明艰难梭菌毒素B（TCDB）的主要毒力因子直接激活ILC3。此外，其他人的工作显示重组IL-22的给药在小鼠CDI模型中提供了保护，这表明在感染期间，在其自然产生的水平上增强细胞因子可以帮助CDI患者。因此，我们正在研究ILC3中的分子途径对于激活很重要，以鉴定新的途径以增强功能。一系列引起人们感兴趣的途径是细胞代谢。我们的初步数据表明多胺正阳性地调节TCDB介导的ILC3的激活。激活的多胺水平增加当抑制关键的生物合成酶时，ILC3会产生较少的IL-22。多胺很重要在转录和翻译中，在其他免疫细胞的激活中具有重要作用，并且尚未完全在ILC3S中进行了研究。中心假设是多胺生物学对于ILC3激活很重要，并且可以利用多胺来改善艰难梭菌感染和/或复发的结局。在此提案中我们将研究代谢途径如何控制ILC3激活，这对这些激活具有可翻译的含义艰难梭菌感染中的免疫细胞。中央假设将通过追求两个具体目标来检验：1）确定艰难梭菌激活C. c. ilc3s中多胺功能的机制，并确定如何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，我们将实现目标，并确定多胺在艰难梭菌介导的ILC3中靶向的细胞途径的无靶方法方法激活。第二个目标将测试如何在体内靶向多胺以增强先天免疫反应从而预防或减少原发性或复发性疾病中的CDI严重程度。完成这些目标后，预期的结果是两个方面的两个方面，因为（1）了解如何理解如何多胺调节ILC3激活，（2）确定多胺如何可翻译潜力在CDI期间利用以提高免疫力。这些结果将对我们对对艰难梭菌的免疫反应将为进一步发展提供强大的循证理由 ILC3和IL-22生物学针对CDI患者的疗法。