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

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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.