DEFINING MECHANISMS UNDERPINNING ANTIBIOTIC MEDIATED DISRUPTION OF PULMONARY IMMUNE RESPONSES

定义抗生素介导的肺免疫反应破坏的机制

• 批准号: MR/Y008812/1
• 负责人: Elizabeth Mann
• 金额: $ 232.01万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY008812%2F1
• 关键词: DEFINING; MECHANISMS; UNDERPINNING; ANTIBIOTIC; MEDIATED

Antibiotics are used to kill dangerous strains of bacteria that cause harmful infections, but are often inappropriately prescribed for diseases in which inflammation rather than a bacterial infection is the main cause. This includes asthma which is believed to be caused by a certain type of inflammation, driven by the immune system, called type 2 inflammation. Work in animal models shows that the harmless bacteria which normally live in tissues such as the gut and the lung are beneficial for a healthy immune system and can protect against harmful type 2 inflammation in the lung. Many of these harmless bacteria are also killed by antibiotics and there is increasing experimental evidence in animal models showing that antibiotics can in fact predispose to type 2 inflammation in the lung, contributing to conditions such as asthma. To date, there have been no studies in humans directly investigating the effects of antibiotics on immune responses in the lung. However individuals who have taken multiple courses of antibiotics earlier in life are more likely to develop asthma. Our pilot data indicate that antibiotic use in animal models alters immune responses in the lung, specifically by activating the immune cells involved in type 2 inflammation. The aim of the current project is to study whether oral antibiotic use has similar effects in humans. We will first investigate whether antibiotics causes healthy individuals to have abnormal immune responses in the lung. We will characterise different types of immune cells from the lungs themselves, and by looking at immune cells in the bloodstream, we will be able to see how the rest of the body may be affected. We will determine whether any changes to the immune system correspond to antibiotic induced changes in populations of harmless bacteria in the gut and the lung. Next, we will investigate whether antibiotics alter immune responses in asthmatic individuals who already have type 2 inflammation in the lung. We will focus on discovering cells, molecules and pathways that are involved in antibiotic-driven alterations of immune responses. This work aims to reveal new strategies that could be used to counteract the harmful side effects of antibiotics. These new pathways also have the potential to shape more targeted treatment in type 2 inflammatory diseases such as asthma, as well as increasing our general understanding of how harmless "friendly" bacteria help control immune responses in the lung.

抗生素用于杀死引起有害感染的危险细菌菌株，但通常不适当地开处方疾病，其中炎症而不是细菌感染是主要原因。这包括哮喘，被认为是由某种类型的炎症引起的，由免疫系统驱动，称为2型炎症。动物模型中的工作表明，通常生活在肠道和肺等组织中的无害细菌对健康的免疫系统有益，并且可以预防肺中有害2型2型炎症。这些无害的细菌中的许多也被抗生素杀死，在动物模型中，实验证据越来越多，表明抗生素实际上可能易于肺中的2型炎症，从而导致诸如哮喘等疾病。迄今为止，尚无人类直接研究抗生素对肺部免疫反应的影响。但是，在生命早期接受多种抗生素课程的人更有可能发展哮喘。我们的试点数据表明，动物模型中的抗生素使用会改变肺中的免疫反应，特别是通过激活涉及2型炎症的免疫细胞。当前项目的目的是研究口服抗生素的使用是否对人类具有相似的作用。我们将首先研究抗生素是否会导致健康个体在肺中具有异常的免疫反应。我们将表征来自肺部本身的不同类型的免疫细胞，并通过查看血液中的免疫细胞，我们将能够看到身体其余部分如何受到影响。我们将确定免疫系统的任何变化是否对应于抗生素引起的肠道和肺中无害细菌种群的变化。接下来，我们将研究抗生素是否改变肺部已经患有2型炎症的哮喘患者的免疫反应。我们将专注于发现与抗生素驱动的免疫反应改变有关的细胞，分子和途径。这项工作旨在揭示可用于抵消抗生素有害副作用的新策略。这些新途径还具有在2型炎症性疾病（例如哮喘）中塑造更靶向的治疗方法的潜力，并提高了我们对无害“友好”细菌如何有助于控制肺中的免疫反应的一般理解。