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.

抗生素是用来杀死导致有害感染的危险细菌菌株的，但通常不适用于炎症而不是细菌感染是主要原因的疾病。这包括哮喘，它被认为是由免疫系统驱动的某种类型的炎症引起的，称为2型炎症。在动物模型上的研究表明，通常生活在肠道和肺部等组织中的无害细菌对健康的免疫系统有益，可以防止肺部有害的2型炎症。许多这些无害的细菌也会被抗生素杀死，而且在动物模型中有越来越多的实验证据表明，抗生素实际上会导致肺部2型炎症，导致哮喘等疾病。迄今为止，还没有在人体中直接调查抗生素对肺部免疫反应的影响的研究。然而，在生命早期服用过多次抗生素的人更有可能患上哮喘。我们的试点数据表明，在动物模型中使用抗生素会改变肺部的免疫反应，特别是通过激活参与2型炎症的免疫细胞。目前项目的目的是研究口服抗生素是否对人类有类似的影响。我们将首先调查抗生素是否会导致健康个体在肺部产生异常的免疫反应。我们将从肺部本身描述不同类型的免疫细胞，通过观察血液中的免疫细胞，我们将能够看到身体的其他部分是如何受到影响的。我们将确定免疫系统的任何变化是否与抗生素引起的肠道和肺部无害细菌种群的变化相对应。接下来，我们将研究抗生素是否会改变已经患有2型肺部炎症的哮喘患者的免疫反应。我们将专注于发现参与抗生素驱动的免疫反应改变的细胞、分子和途径。这项工作旨在揭示新的策略，可以用来抵消抗生素的有害副作用。这些新的途径也有可能在2型炎症性疾病（如哮喘）中形成更有针对性的治疗，并增加我们对无害的“友好”细菌如何帮助控制肺部免疫反应的一般理解。