Probing the sequence of cellular activation by rhinoviral infection in the airway and identifying how this may be dysregulated in COPD

Chronic obstructive pulmonary disease (COPD) is the term used to describe a number of conditions affecting the lungs, including chronic bronchitis and emphysema. It is a leading cause of morbidity and disability, and is predicted to become the fourth leading cause of death globally by 2030. COPD sufferers are highly susceptible to acute exacerbations (a sudden worsening of symptoms) triggered by chest infections; with rhinoviruses (which cause the common cold) the most frequently identified cause. Acute exacerbations often require treatment in hospital and are a major medical burden for COPD patients, doctors and healthcare organisations. Why the airways of COPD patients are highly responsive to rhinoviral infection is currently unknown, and determining the answer is the aim of this research proposal.

When we inhale rhinoviruses (RV) they come into contact with and infect the cells lining the surface of the lung, which are known as epithelial cells. Understanding how the epithelial cells detect RV infection is of great importance as this is essential to allow the body to respond appropriately to the viral infection. Limited research suggests a cellular process called 'autophagy' may be involved in viral detection. Our preliminary data supports this, and reveals that stopping autophagy in human epithelial cells reduces their ability to respond to RV infection. In this study our first aim is to build on these findings: determining the role of autophagy in controlling the epithelial cells ability to (a) detect RV, (b) mount an appropriate inflammatory response, and (c) control the production of new virus. Interestingly, a previous study has shown that lung tissues taken from patients with COPD show a higher level of autophagy than tissues from healthy people. Therefore the second aim of this work is to establish if RV infection is controlled differently in the COPD airway due to an enhanced capacity for autophagy. This will be investigated using lung epithelial cells obtained from COPD patients via the Sheffield Lung Research Tissue Bank. These cells will also be used to ascertain if the genes that control autophagy show altered expression or function in epithelial cells from COPD sufferers. Genes hold the body's genetic information and changes to these genes can cause, or leave people more susceptible to, disease. The final aim of this study is to explore two potential pathways that affect COPD and have been identified as causing enhanced autophagy in cells. The first is the cytokine Interleukin-1 (IL-1), which causes inflammation and is present at higher levels in COPD. We have also published that IL-1 dramatically enhances epithelial cell responses to RV. The second is hypoxia, or oxygen depletion, which may be an important feature of the damaged lung in COPD. These pathways will be studied to determine if they enhance autophagy and alter RV infection in a manner analogous to that observed in COPD cells.

This research will therefore comprehensively explore a previously unidentified role for autophagy in regulating the response of lung epithelial cells to viral infection, both in health and during disease. Identifying specific autophagic genes and pathways that are altered in COPD will assist in the discovery and development of novel therapeutics for this complex disease. The results obtained from this project will therefore provide invaluable information to both the research community and industry, advance the field of COPD research, and in due course help patients with COPD.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and disability globally. Human rhinoviruses (RV) are a frequent trigger of acute exacerbations in COPD patients, and contribute considerably to the healthcare and economic burden of this disease. Whilst the receptors responsible for RV detection within human bronchial epithelial cells (HBECs) are known, how endosomal pattern recognition receptors (PRRs) detect RV replication products that are generated within the cytoplasm remains somewhat of an enigma. This study will explore autophagy as the crucial mechanism controlling this process. Our preliminary data reveals that inhibition of autophagy significantly reduces RV-induced cytokine generation in HBECs. Initial work will build on these findings, determining the role of autophagy in modulating the response of HBECs to RV infection, probing its function in viral presentation to PRRs and the resulting effects on viral-induced cytokine generation and prodigy virion production. The autophagic pathway is reportedly augmented in the COPD airway. HBECs from COPD patients and control subjects will therefore be utilised to establish if RV infection is controlled differently in COPD airway epithelial cells due to differences in autophagy. Key autophagy genes and cellular pathways that are dysregulated in COPD will subsequently be identified. This research will therefore comprehensively explore a previously unidentified role for autophagy in regulating the innate immune response of airway epithelial cells to viral infection, both in health and during disease. It is believed that changes to the autophagic pathway in the COPD airway will alter the susceptibility and response to viral infection during acute exacerbations, resulting in increased inflammation with deleterious consequences. Identifying specific genes and pathways that are dysregulated in COPD will thus assist in the future development of novel therapeutics for this complex disease.

Who will benefit from this research?
This research aims to understand how viruses aggravate respiratory diseases, and identify specific genes and pathways that are dysregulated in the chronic obstructive pulmonary disease (COPD) airway. The ultimate aim is to assist in the future development of novel therapeutics to reduce the morbidity or mortality of this complex disease. Given the large and growing healthcare and economic burden of COPD there are multiple and wide-ranging prospective beneficiaries of this work, both within the UK and globally:
1. COPD patients.
2. Respiratory clinicians and healthcare establishments.
3. Companies developing pharmacological therapies and managing clinical trials.
4. Academia.
5. General public and the third sector (charities, voluntary organisations).

How will they benefit from this research?
COPD is a leading cause of morbidity and disability, and is predicted to become the fourth leading cause of death globally by 2030. COPD sufferers are highly susceptible to acute exacerbations (a sudden worsening of symptoms) triggered by chest infections. Rhinovirus, the cause of the common cold, is the most frequently identified virus. Acute exacerbations represent a major medical issue for COPD patients, clinicians and healthcare establishments. Patients often require hospitalisation and can be difficult and costly to manage medically.
Why the airways of COPD patients have an altered responsiveness to rhinoviral infection is currently unknown, and determining the answer is the aim of this research proposal. Further insight into the basic mechanisms involved will benefit academia and companies with an interest in COPD, allowing further scientific advances in the area. In addition, understanding of the specific genes and pathways that are dysregulated in COPD will generate novel targets for pharmacological therapies to direct or tune the bodies response to virally-induced disease and thus reduce acute exacerbations. We will ensure any potential therapeutic targets identified by this research are exploited to their full potential during the three year research grant period and beyond. This will require collaboration with appropriate companies and the creation of clinical trials. Of note we already have established links with GlaxoSmithKline in the form of a PhD studentship, working on a distinct project that also aims to better understand COPD. The ultimate aim of this project is to reduce the susceptibility of COPD patients to acute exacerbations, and thus improve their quality of life whilst concurrently reducing the burden on the healthcare system.
Patient and public awareness and understanding of COPD and other respiratory diseases is often limited. Dr Parker will initiate and oversee the creation of a webpage within the Department of Infection & Immunity, which will detail in lay terms the research associated with the Sheffield Lung Research Tissue Bank and will enable patients and their family members to have greater access to information when making the decision to donate tissue. By promoting the website to the general public and providing links to charities and voluntary organisations, a greater understanding of research within the field of respiratory medicine will be gained. The website will also provide a forum for engaging local potential beneficiaries with the research carried out in Sheffield, via methods such as public open days, seminars and workshops. This will maximise the impact of the research undertaken in this grant on COPD patients, the general public, and the third sector, offering potential benefits to multiple groups.
Patients and the general public are likely to benefit almost immediately from the plans to significantly enhance communication of, and engagement with, this research. The development of novel therapeutic targets, which will benefit COPD patients, clinicians, healthcare establishments and companies, is a long term but ultimately achievable goal.