Experimental viral challenge in bronchiectasis to study the immunopathogenesis of exacerbations

支气管扩张是一种慢性肺部疾病，在英国影响超过20万人。该疾病的特征是对症状性发作（恶化）的进行性易感性。这些发作是发病和死亡的主要原因，治疗选择有限。从历史上看，细菌被认为是大多数急性加重的原因，导致广泛使用长期抗生素（其作用是特异性地对抗细菌）进行治疗。然而，细菌对许多抗生素的耐药性越来越强，我们迫切需要新的治疗方法。我们最近发现，与以前的观点相反，相当大比例的急性加重（约40%）与病毒（最常见的是鼻病毒）的检测有关，这可能是支气管扩张急性加重的未识别触发因素。这一点在COVID-19大流行期间得到了强调，当时支气管扩张症的恶化率显著下降，据信这是由于个人之间的社交互动减少，限制了他们接触传播病毒。尽管有这些提示性的证据，但病毒是否能直接引发支气管扩张症的恶化仍不清楚，使这些个体易受病毒感染的机制也不清楚。故意用鼻病毒感染支气管扩张受试者是否会导致病情加重？2.支气管扩张是否会降低免疫系统对病毒感染的反应和抵抗能力？3.在病毒感染导致支气管扩张恶化期间，肺部发生了什么变化？这项研究将由帝国理工学院、邓迪大学、南安普顿大学和南洋理工大学（新加坡）的合作科学家进行。我们将鼻病毒注入36名支气管扩张症受试者和18名健康对照受试者的鼻子中以诱导感染。我们将记录呼吸道症状，并在此之后每天测量肺功能，以确定鼻病毒感染是否会导致支气管扩张症的症状比健康个体更严重。我们将从这些人的鼻子和咳出的粘液中提取样本，以测量免疫系统在气道中产生的物质的浓度，以对抗病毒感染（称为“干扰素”等物质）。我们还将使用支气管镜检查（将望远镜插入气道以获得深层样本的测试）从这些人的肺部获取细胞。我们将在实验室中培养这些细胞，用鼻病毒感染它们，然后再次测量它们产生多少干扰素和其他物质。这将确定支气管扩张症是否与免疫系统对病毒感染的反应能力降低有关。我们以前曾成功地在其他慢性肺部疾病（哮喘和COPD）受试者中进行了类似的鼻病毒感染研究，具有良好的安全性。这些研究使我们能够了解病毒在触发急性加重中的重要性及其相关机制。该项目将首次在支气管扩张症中建立类似的模型，并使我们能够了解哪些是这些患者中产生的较低数量的关键免疫物质。这将使我们能够进行未来的研究，我们检查是否将这些物质直接施用到支气管扩张症患者的肺部（例如使用吸入器）可以在暴露于病毒时增强他们的免疫反应，从而防止病情加重。我们将开发的模型将为测试这些类型的方法提供完美的平台。总之，这项研究将为一个具有巨大临床重要性的领域提供新的科学见解，并促进开发令人兴奋的新疗法，以减轻支气管扩张引起的疾病负担。

Bronchiectasis is a chronic lung condition that affects over 200,000 individuals in the UK. The disease is characterised by progressive susceptibility to symptomatic flare-ups (exacerbations). These episodes are a major cause of morbidity and mortality with limited treatment options. Historically, bacteria have been deemed responsible for most exacerbations leading to widespread treatment with prolonged antibiotics (which act to specifically counteract bacteria). However, bacteria are increasingly becoming resistant to many antibiotics and we urgently need new approaches.We have recently found that, contrary to previous belief, a significant proportion of exacerbations (~40%) are associated with detection of viruses (most commonly rhinovirus) which may be an unrecognised trigger for bronchiectasis exacerbations. This was highlighted during the COVID-19 pandemic where there was a striking reduction in bronchiectasis exacerbation rates believed to be due to reduced social interactions between individuals which limited their exposure to circulating viruses. Despite this suggestive evidence, it remains unclear whether viruses can directly trigger exacerbations in bronchiectasis and the mechanisms that predispose these individuals to viral infections are unknown.This project asks the following three questions:1. Does deliberately infecting bronchiectasis subjects with rhinovirus lead to development of an exacerbation?2. Does bronchiectasis reduce the immune system's ability to respond to and fight off viral infection?3. What are the changes that occur in the lungs during a viral infection that lead to bronchiectasis exacerbation?This research will be carried out by collaborating scientists at Imperial College, University of Dundee, University of Southampton and Nanyang Technological University (Singapore). We will administer rhinovirus into the nose of 36 subjects with bronchiectasis and 18 healthy control subjects to induce infection. We will record respiratory symptoms and also measure lung function daily following this, to determine whether rhinovirus infection causes a greater flare-up of symptoms in bronchiectasis compared to healthy individuals. We will take samples from the nose and also mucus coughed up by these individuals to measure concentrations of substances that are produced in the airways by the immune system to combat viral infections (substances called 'interferons' and others). We will additionally take cells from the lungs of these individuals using bronchoscopy (a test where a telescope is inserted into the airways to gain deep samples). We will culture these cells in the laboratory and infect them with rhinovirus before again measuring how much interferon and other substances they produce. This will determine if bronchiectasis is associated with a reduced ability of the immune system to respond to a viral infection.We have previously successfully carried out similar rhinovirus infection studies in subjects with other chronic lung diseases (asthma and COPD) with an excellent safety profile. These studies allowed us to understand the importance of viruses in triggering exacerbations and the mechanisms involved. This project will establish a similar model for the first time in bronchiectasis and allow us to understand which are the key immune substances that are produced in lower quantities in these patients. This would then allow us to conduct future studies where we examine whether administering these substances directly into the lungs of patients with bronchiectasis (e.g. using an inhaler) could boost their immune response when exposed to viruses and thereby prevent exacerbations. The model we will develop would provide the perfect platform to test these types of approaches. In summary, this research will provide new scientific insight into an area of huge clinical importance and facilitate the development of exciting new therapies to reduce the burden of disease caused by bronchiectasis