The Impact and Regulation of IL-6 in Clostridioides difficile Infection

IL-6在艰难梭菌感染中的影响及调控

• 批准号: 10656400
• 负责人: David Tyus
• 金额: $ 3.72万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656400
• 关键词: Address; Adrenergic Agents; Anti-Inflammatory Agents; Antibiotics; Antiinflammatory Effect; Attention; Binding; Bone Marrow; Catecholamines; Cells; Cessation of life; Chimera organism; Clinical; Clostridium difficile; Communicable Diseases; Data; Disease; Disease Progression; Elderly; Epinephrine; Epithelium; Functional disorder; Genetic Transcription; Gram-Positive Bacteria; Hematopoietic; Immune; Immune response; Immunity; Immunophenotyping; Immunotherapy; Infection; Inflammation; Inflammatory; Interleukin-6; Macrophage; Mediating; Modeling; Monitor; Mus; Neurotransmitter Receptor; Norepinephrine; Nosocomial Infections; Outcome; Pathogenesis; Pathology; Patients; Persons; Production; Proteins; Receptors, Adrenergic, alpha-2; Regulation; Research; Risk; Role; Sanitation; Severities; Severity of illness; Signal Pathway; Signal Transduction; Source; Symptoms; Testing; Therapeutic; Tissues; Wild Type Mouse; Work; alpha-adrenergic receptor; diarrheal disease; enteric infection; epithelium regeneration; experimental study; fortification; gut microbiota; immunoregulation; innovation; mortality; mouse model; neutralizing antibody; novel therapeutics; pathogen; pharmacologic; recurrent infection; regenerative; response; therapeutic evaluation

Project Summary Clostridioides difficile is a Gram-positive bacterium responsible for more hospital-acquired infections than any other pathogen. C. difficile infection (CDI) manifests in a range of severity from diarrheal illness to death, especially in advanced aged patients. Current therapy for CDI largely relies on antibiotics and, while effective short term, greatly increases the risk for recurrent infection. To address this issue, we look to identify immunomodulatory approaches that spare the protective gut microbial communities. In this proposal I will interrogate the role of IL-6 in CDI disease progression. In preliminary experiments, we found that neutralizing IL-6 worsened disease symptoms in our CDI murine model, suggesting a protective role for IL-6 in CDI. Further, we found that transcription of a neurotransmitter receptor and positive regulator of IL-6, the alpha 2 adrenergic receptor(a2ar), is decreased in severe CDI as compared to mild CDI. Norepinephrine and epinephrine can bind a2ar in immune cells to increase their production of IL-6. Released IL-6 can act through two signaling pathways: trans-signaling and classical signaling. IL-6 trans-signaling typically causes pro-inflammatory effects while classical signaling tends to have anti-inflammatory, regenerative effects. We hypothesize that IL-6 acts through classical signaling to induce epithelial regeneration and, in turn, decrease disease severity in CDI. To test this hypothesis, I will use a murine model of CDI. In Aim 1 I will investigate the role of IL-6 and determine if classical or trans-signaling pathways dictate the effect of IL-6 by monitoring disease severity and inflammatory profile in models deficient in IL-6 activity or stimulated or deficient in trans-signaling. In Aim 2, I will identify the primary cellular source of IL-6 during CDI and determine whether IL-6 production is regulated by catecholamines norepinephrine and epinephrine in this context. Together, these data will allow us to consider the signaling axes and cellular determinants that are potentially targetable in CDI. This work not only has implications for CDI therapy but more broadly, it will allow us to understand the contributing factors to the pleiotropic role of IL-6 in the gut.

项目摘要 艰难梭菌是一种革兰氏阳性菌， 比任何其他病原体都多。C.艰难梭菌感染（CDI）表现为一系列严重程度 尤其是高龄患者。CDI的当前治疗方法 在很大程度上依赖于抗生素，虽然短期有效，但大大增加了 复发性感染为了解决这个问题，我们希望确定免疫调节方法 保护性肠道微生物群落。在这个建议中，我将询问 IL-6在CDI疾病进展中的作用在初步实验中，我们发现中和IL-6 在我们的CDI小鼠模型中，疾病症状恶化，表明IL-6在CDI小鼠模型中的保护作用。 CDI.此外，我们发现，神经递质受体和正调节因子的转录， IL-6，α 2肾上腺素能受体（α 2ar），与轻度CDI相比，在重度CDI中降低 CDI.去甲肾上腺素和肾上腺素可以结合免疫细胞中的A2 AR以增加其产生 IL-6释放的IL-6可以通过两种信号通路起作用：反式信号通路和经典信号通路。 发信号。IL-6反式信号传导通常引起促炎作用，而经典信号传导通常引起促炎作用。 有抗炎和再生的作用我们假设IL-6通过 经典的信号传导，以诱导上皮再生，并反过来降低疾病的严重程度， CDI.为了验证这一假设，我将使用CDI的小鼠模型。在目标1中，我将研究 的IL-6，并确定是否经典或反式信号传导途径决定的IL-6的作用， 监测IL-6活性缺陷模型中的疾病严重程度和炎症特征，或 反式信号被刺激或缺乏。在目标2中，我将确定 CDI过程中IL-6的产生，并确定IL-6的产生是否受儿茶酚胺的调节 去甲肾上腺素和肾上腺素这些数据将使我们能够考虑 CDI中潜在靶向的信号轴和细胞决定因素。这项工作不 它只对CDI治疗有影响，但更广泛地说，它将使我们了解 IL-6在肠道中的多效性作用的促成因素。