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

项目摘要 艰难梭状芽孢杆菌是一种革兰氏阳性细菌，导致医院获得性更多 感染比任何其他病原体都多。艰难梭菌感染(Cdi)表现为一系列严重程度。 从腹泻病到死亡，特别是高龄患者。CDI的当前治疗方法 在很大程度上依赖于抗生素，虽然在短期内有效，但极大地增加了 反复感染。为了解决这个问题，我们希望确定免疫调节方法 这样就避免了肠道微生物群落的保护。在这项提议中，我将审问 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，提示IL-6在 CDI公司。此外，我们发现一种神经递质受体和正性调节因子的转录 IL-6，α2肾上腺素能受体(A2ar)，在重度CDI与轻度CDI相比降低。 CDI公司。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的表达。释放的IL-6可以通过两种信号途径发挥作用：反式信号和经典信号 发信号。IL-6反式信号转导通常导致促炎效应，而经典信号转导 往往具有消炎、再生的作用。我们假设IL-6通过 经典信号诱导上皮再生，进而降低疾病严重程度 CDI公司。为了验证这一假设，我将使用CDI的小鼠模型。在《目标1》中，我将调查这个角色 确定经典或转导信号通路是否通过以下方式决定IL-6的作用 监测IL-6活性或IL-6活性缺乏的模型的疾病严重程度和炎症情况 在转导信号方面受到刺激或缺乏。在目标2中，我将确定主要的细胞来源 CDI期间的IL-6，并确定IL-6的产生是否受儿茶酚胺的调节 本文中的去甲肾上腺素和肾上腺素。综合起来，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。这项工作不是 只对CDI治疗有影响，但更广泛地说，它将使我们了解 影响IL-6在肠道中的多效性的因素。

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.