Targeting microRNAs to restore airway epithelium integrity after respiratory viral infection in asthma patients

Over 5.4 million people in the UK suffer from asthma. The total economic cost of asthma in the UK was estimated to be £6 billion in 2023. A small population of patients (5-10%) in the UK have severe asthma, who need more specific treatments to control their symptoms, and that accounts for 65% of asthma healthcare budget, annually. Severe asthma affects the patients' quality of life to a level that is considered a disability in the UK. Different triggers including, respiratory viruses make it harder for asthma patients to breathe (asthma attack). Particularly in severe asthma, even when the disease is under control by taking optimal doses of medications, respiratory viruses can cause asthma attacks, leading to hospitalisation and even death. Vaccination is the major protection against viruses like flu, however its effectiveness is challenged by new strains of viruses. No specific treatment can significantly amend the clinical outcome related to asthma attacks after flu infection. Our goal is to address this unmet need by detecting specific markers that predict asthma attacks due to flu, and identifying more effective targets for interventions. People with asthma have sensitive airways that make it more difficult for them to breathe. The outer lining layer of the airway is called the epithelium which is made of epithelial cells. Airway epithelium is the first protective barrier between flu virus and the internal environment of lungs. In asthma patients, epithelium fails to defend against flu. The flu virus further damages the epithelium, causing asthma attacks. The airway epithelium represents a good resource for identifying markers predicting asthma attacks, and a good therapeutic target. While multiple genetic factors are involved in the development of asthma, it is the impact of the environment on genes that explains much of the variation seen in the disease. Our focus is therefore on how external environmental factors (flu virus) affect genes' products (mRNAs) through specific markers, known as microRNAs. To achieve our goals, we will evaluate these markers (microRNAs) which control genes' products (mRNAs) responsible for the airway epithelium damage, after flu infection. We will deliver our research in 4 steps. During steps-1,2&3, we will obtain epithelial cells from severe asthma patients and healthy participants in the clinic. In the laboratory, we will grow these cells in similar conditions to the human body and infect them with flu virus to mimic what happens to epithelial cells in the patients' airways who have flu. We will then compare the global microRNAs (markers) and mRNAs (genes products) in cells obtained from asthma patients, with and without infection with those from healthy donors (step-1). Hence we will detect markers that are specifically affected genes products responsible for epithelial damage in asthma before and after flu infection. We thereafter investigate the role of specific microRNAs, and their targets (genes products) in cells from asthma patients (step-2) to be able to restore airway epithelial integrity after flu infection (step-3). Finally, we will confirm our findings using lung slices obtained from asthma patients and healthy participants (step-4). We will use state-of-art technologies of tissue culture, gene sequencing, and protein detection techniques. These enable us to provide specific markers that may predict or be used as potential new treatment targets for asthma attack after flu infection, to reduce the winter NHS burden and improve patients care in future.