The role of neutrophils in viral-induced asthma exacerbations

Abstract

Asthma is a chronic respiratory condition effecting approximately 10% of the Australian population and contributing to significant healthcare costs per annum. Patients experience a range of respiratory symptoms from chest tightness and wheeze to excess mucus production and coughing. Generally, people with asthma have stable disease interspersed with periods of worsening symptoms known as exacerbations. Exacerbations range from mild airway narrowing leading to complete closure of areas of the lungs and can be precipitated by a number of triggers including allergens, pollution and infections. Exacerbations can be life threatening events in certain individuals. Asthma is characterised by reversible airway limitation, airway hyper-reactivity, airway remodelling, but most importantly chronic inflammation. Chronic inflammation is believed to be the underlying dysfunction that results in the hallmarks of this disease. A multitude of inflammatory cells may infiltrate the airways of patients with asthma which classically are mast cells and eosinophils. However it is now recognised many other immune cells are recruited including neutrophils and monocytes, which are the focus of this thesis. In addition to immune cell infiltrate, there is also upregulation of inflammatory cytokines and mediators which is thought to be involved in the pathogenesis of asthma exacerbations. It has been established that inflammation of the airways is elevated in asthmatics and it is raised even further during times of exacerbations. However, the source and the mechanisms driving dysregulation of these inflammatory mediators are unclear. The most common trigger for asthma exacerbations are respiratory viral infections. In particular, rhinovirus (RV) infections are the most commonly detected virus in exacerbating asthmatics and therefore we believed it was the most important virus to investigate in this thesis. RV is a highly contagious and prevalent pathogen due to its ability to change immunogenic sites quickly and hence evade the immune system. For this reason, it poses a consistent problem for asthmatics as immunity against this virus is near impossible. The mechanisms behind how RV causes exacerbations remains unknown but it is believed to be at least in part due to inflammatory responses produced in response to the virus. Whilst inhaled corticosteroids help reduce airway inflammation and subsequently prevent worsening of symptoms, they cannot completely prevent acute exacerbations occurring in these patients. To date, the exact mechanisms that drive the pathogenesis of asthma are unclear, however, a number of theories exist. From a clinical perspective, it is known that factors in early life such as development of wheeze and family history of asthma increase the risk of developing asthma later in life. One of the most common causes of wheeze in infants is respiratory viral infections particularly rhinoviruses (RV) and respiratory syncytial virus (RSV). It is unclear if such children are more susceptible to developing wheeze or if infection causes wheeze. Furthermore, does infection with viruses prime the immune system to be chronically active later in life? Or do viruses help identify which individuals have dysregulated immune responses that result in more severe infections? Neutrophils are the most abundant immune cell in the body and are vital for combating infections. They are highly mobile cells that follow chemotactic gradients towards sites of infection and mediate classical effector functions such as phagocytosis of the pathogen and degranulation of proteases and antimicrobial products. More recently, it is apparent that neutrophils are capable of many more functions to combat infections such as the release of sticky nets to trap pathogens and interaction with the adaptive immune system. Neutrophils are primarily known for their pro-inflammatory roles and many other chronic inflammatory diseases, including asthma, are characterised with neutrophilia and neutrophilic inflammation.