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: 10471813
• 负责人: David Tyus
• 金额: $ 3.6万
• 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/10471813
• 关键词: ADORA2A gene; 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; Epithelial; Functional disorder; Genetic Transcription; Gram-Positive Bacteria; Hematopoietic; Immune; Immune response; Immunity; Immunophenotyping; Immunotherapy; Infection; Inflammation; Inflammatory; Interleukin-6; Mediating; Modeling; Monitor; Mus; Neurotransmitter Receptor; Norepinephrine; Nosocomial Infections; Outcome; Pathogenesis; Pathology; Patients; Persons; Pharmacology; 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; base; diarrheal disease; enteric infection; epithelium regeneration; experimental study; fortification; gut microbiota; immunoregulation; innovation; macrophage; mortality; mouse model; neutralizing antibody; novel therapeutics; pathogen; 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.

项目概要 艰难梭菌是一种革兰氏阳性细菌，导致更多医院获得性感染 感染率高于任何其他病原体。艰难梭菌感染 (CDI) 表现出多种严重程度 从腹泻病到死亡，尤其是老年患者。目前 CDI 的治疗方法 很大程度上依赖抗生素，虽然短期有效，但大大增加了感染的风险 反复感染。为了解决这个问题，我们希望找到免疫调节方法 从而保护肠道微生物群落的保护性。在这个提案中，我将询问以下角色： 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。此外，我们发现神经递质受体的转录和正调节因子 与轻度相比，重度 CDI 患者的 IL-6（α2 肾上腺素能受体 (a2ar)）减少 CDI。去甲肾上腺素和肾上腺素可以结合免疫细胞中的a2ar以增加其产量 IL-6。释放的 IL-6 可通过两种信号传导途径发挥作用：反式信号传导和经典信号传导 发信号。 IL-6 反式信号转导通常会引起促炎作用，而经典信号转导通常会引起促炎作用 往往具有抗炎、再生作用。我们假设 IL-6 的作用是通过 诱导上皮再生的经典信号传导，进而降低疾病的严重程度 CDI。为了验证这个假设，我将使用 CDI 小鼠模型。在目标 1 中，我将调查角色 IL-6 并确定经典或反式信号传导途径是否决定 IL-6 的作用 监测缺乏 IL-6 活性的模型中的疾病严重程度和炎症特征，或 转信号受到刺激或缺乏。在目标 2 中，我将确定以下物质的主要细胞来源： CDI 期间的 IL-6 并确定 IL-6 的产生是否受儿茶酚胺调节 在这种情况下，去甲肾上腺素和肾上腺素。这些数据共同使我们能够考虑 CDI 中可能靶向的信号轴和细胞决定因素。这项工作不 只对 CDI 治疗有影响，但更广泛地说，它将使我们了解 IL-6 在肠道中发挥多效作用的影响因素。