Investigating the antimicrobial efficacy of mesenchymal stromal cells as a novel potential therapy for Mycobacterium avium pulmonary infection

问题：鸟分枝杆菌引起的胸部感染每年都有越来越多的患者被诊断为由一组被称为“非结核分枝杆菌”（NTM）的细菌引起的胸部感染。这些细菌生活在环境中，通常只影响患有慢性胸部疾病（如支气管扩张症、慢性阻塞性肺病和囊性纤维化）或严重免疫疾病（如原发性免疫缺陷症）的人。然而，患者也可能因使用抑制免疫系统的药物而处于危险之中。这些药物包括抗肿瘤坏死因子制剂，越来越多地用于治疗常见疾病，如类风湿关节炎、多发性硬化症和克罗恩病。众所周知，类固醇吸入器也会降低对抗胸部感染的能力，尤其是慢性阻塞性肺病患者。慢性疾病患者预期寿命的增加以及这些免疫抑制药物的使用意味着NTM胸部感染的病例数预计会上升。在英国，鸟分枝杆菌（M. avium）是非结核性分枝杆菌胸部感染的增长最快的原因。它尤其令人担忧，因为它很难诊断，而且对抗生素具有很强的耐药性。一旦鸟支原体在病人的胸部扎根，就很难根除。感染会导致持续的症状，如咳嗽、咳痰和体重减轻。如果不治疗，肺组织可能会逐渐被破坏，患者可能需要长期的氧气治疗。目前治疗鸟分枝杆菌胸部感染的最佳方法是大约18个月至少服用三种抗生素。大多数患者不能很好地耐受这些抗生素，只有大约60%的病例能够治愈。因此，迫切需要开发一种治疗鸟分枝杆菌胸部感染的新方法，这种方法耐受性更好，治愈速度更快。研究思路：一种新的基于细胞的鸟分枝杆菌治疗方法我们的目的是研究一种利用人细胞间充质基质细胞（MSCs）治疗鸟分枝杆菌感染的新的潜在疗法。间充质干细胞是我们身体通常产生的细胞，可以修复损伤，阻止炎症，帮助杀死一些细菌。它们已被用于临床试验，以测试它们对COPD和特发性肺纤维化患者的肺功能的帮助作用，并被发现是安全的。我们已经在实验室做了一些实验来测试它们杀死鸟支原体的能力，初步结果非常有希望。早期的研究已经提出了MSCs杀死其他细菌的多种可能方式，比如释放抗菌因子和增强被称为巨噬细胞的免疫细胞。我们想看看M - avium是否也是如此。在这个项目中，我们将在实验室中研究巨噬细胞如何与鸟分枝杆菌相互作用，并观察MSCs对它们杀死鸟分枝杆菌的能力有什么额外的影响。我们希望揭示MSCs如何帮助杀死鸟分枝杆菌的确切机制，因为这可能使我们能够促进这一机制并提高它们的抗菌效果。如果我们能够证明MSCs具有显著的M. avium杀伤效果，我们将按照这个项目计划进行临床试验，以测试它们在NTM胸部感染患者中的效果。因此，这个项目很重要，因为它可以为这些非常困难的胸部感染提供新的、更快、更好的治疗方法，并提高患者的生活质量。

The Problem: Chest infections with Mycobacterium avium Every year rising numbers of patients are diagnosed with chest infections caused by a group of bacteria called 'non-tuberculous mycobacteria' (NTM). These bacteria live in the environment and usually only affect people with chronic chest disease (such as bronchiectasis, COPD and cystic fibrosis) or with severe immunity disorders (such as primary immunodeficiency). However patients can also be put at risk through the use of drugs that suppress the immune system. These drugs include anti-TNF agents which are increasingly being used for common conditions such as rheumatoid arthritis, multiple sclerosis and Crohn's disease. Steroid inhalers are also known to reduce ability to fight chest infections, particularly in patients with COPD. The increasing life expectancy of people with chronic illnesses and use of these immune-suppressing drugs means that case numbers of NTM chest infections are expected to rise. Mycobacterium avium (M. avium) is the fastest-growing cause of non-tuberculous mycobacterial chest infections in the UK. It is particularly concerning because it is difficult to diagnose and very resistant to antibiotics. Once M. avium is established in a patient's chest, it is very difficult to eradicate. Infection leads to persistent symptoms such as cough, sputum production and weight loss. If not treated, lung tissue can be gradually destroyed and patients may need long-term oxygen therapy. The current best treatment for M. avium chest infection is approximately 18 months of at least three antibiotics. These antibiotics are not well tolerated by the majority of patients and only around 60% of cases will be cured. Therefore there is an urgent need to develop a new way to treat M. avium chest infections that is better tolerated and achieves a quicker cure. The Research Idea: a new cell-based therapy for Mycobacterium avium Our aim is to investigate a new potential therapy for M. avium infections using human cells known as mesenchymal stromal cells (MSCs). MSCs are cells that our bodies normally make which can repair damage, stop inflammation and help kill some bacteria. They have been used in clinical trials to test their effect on helping lung function in patients with COPD and Idiopathic Pulmonary Fibrosis, and found to be safe. We have already done some experiments in the laboratory to test their ability to kill M. avium and preliminary results are very promising. Earlier studies have suggested a number of possible way that MSCs can kill other bacteria, such as releasing antimicrobial factors and boosting immune cells called macrophages. We want to see if this is the case for M avium.For this project we will study how macrophages interact with M. avium in the laboratory and see what additional effect MSCs have on their ability to kill M. avium. We want to uncover the precise mechanism of how MSCs help to kill M. avium as this may allow us to boost that mechanism and improve their antibacterial effect.If we can show MSCs have significant M. avium killing effect, we will follow this project by planning a clinical trial to test their effect in patients with NTM chest infections. Therefore this project is important because it could pave the way for new, faster and better treatments for these very difficult chest infections and improve patients' quality of life.