- Title
- Understanding the pathogenesis of common respiratory virus and infection-induced exacerbation of asthma
- Creator
- Liu, Xiaoming
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2022
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Asthma is a prevalent chronic airway disease, and there is currently no cure. Asthma exacerbations are the worsening symptoms of asthma and are often refractory, even with mainstay asthmatic therapy such as steroids treatment, and can be life-threatening which may require emergency department visit or hospitalisation. Asthma exacerbations can be triggered by different etiological factors, such as allergens and environmental pollutants, while the respiratory viruses are the most common triggers associated with asthma exacerbation. The most common viral pathogens in asthmatic exacerbations are rhinovirus (RV), followed by respiratory syncytial virus (RSV) and influenza virus (FLU). The seasonal nature of these viral pathogens also results in seasonal asthma exacerbations, which occur cyclically in both adults and children. Respiratory viral infection significantly increases asthma morbidity and mortality, resulting in a significant financial burden on healthcare systems. The treatment of asthma exacerbation is currently limited to inhaled or systematic steroid treatment and bronchodilators. However, the efficacy of them in the treatment of viral-induced asthma exacerbation is poor. Thus, there is an urgent need to develop improved therapeutic strategies for asthma exacerbation induced by viral infections. Biologic therapy, which targets one or more key regulators of type 2 inflammation pathway, has been shown to be effective in the treatment of allergic asthma; however, these treated patients may still experience exacerbation and not all asthmatics have a dominate type 2 inflammatory response, particularly viral-induced exacerbation of asthma. Thus, an improved understanding of severe inflammation induced by respiratory viruses is required to identify new potential therapeutic targets. To address this unmet need, we developed in vivo models of viral induced airway disease to assess the effect of infections of the three most common respiratory viruses, FLU, RV and RSV, on pulmonary pathophysiology and in the induction of asthma like exacerbations. Our aim was to better understand the pathogenetic mechanisms and with a view to identify shared mechanisms underlying the airway inflammation associated with these three viruses, to identify a common target to treat asthma exacerbations. This thesis includes three papers. The first paper, “IL‐17A is a common and critical driver of impaired lung function and immunopathology induced by influenza virus, rhinovirus and respiratory syncytial virus. Published in Respirology, DOI:10.1111/resp.14141. The second paper, “The roles of mcp-1 in regulating rhinovirus and influenza-induced asthma exacerbation”, is being prepared for submission. The third paper, “Proteomic analysis reveals a novel therapeutic strategy using Fludarabine for steroid-resistant asthma exacerbation” has been published in Frontiers in Immunology, DOI:10.3389/fimmu.2022.805558. The first paper examines the relationship between the induction of inflammation and the development of immunopathological lung lesions and impaired lung function during RV, RSV or FLU viral infections. Interleukin (IL)-17A was identified as the common factor coordinating these events. This provided an improved understanding of how respiratory infections induce lung dysfunction and the type and site of mechanical disruption within the pulmonary compartment. Allergen-induced asthmatic inflammation is characterised by increased eosinophils, mast cells and goblet cells, leading to mucous hyperplasia. Viral infections are thought to exacerbate asthma by enhancing airway inflammation and/or over activation of the innate immune response. The activation of innate immune cells, including neutrophils and macrophages, has been associated with steroid-resistant asthma exacerbation. Monocyte chemoattractant protein (MCP)-1) has been identified as a prominent factor associated inflammation in RSV-induced asthma exacerbation. Therefore, in the second paper, we investigated whether MCP-1 also plays a pro-inflammatory role in RV- and FLU-induced asthma exacerbation. We found that although MCP-1 was commonly elevated in all viral infection induced asthma exacerbations, the regulating pathways were distinct. Targeting MCP-1 significantly suppressed airway inflammation in RV-induced asthma exacerbation but was only partially beneficial in FLU-induced asthma exacerbation. FLU-induced asthma exacerbation is the most refractory of these virus-induced exacerbations and responds poorly to steroid therapy. Therefore, in the third paper, to gain a deeper insight into the pathogenesis of FLU-induced asthma exacerbation, we applied whole lung proteomic analysis of FLU-induced steroid resistant exacerbation of asthma in a mouse model. Through protein profiling and bioinformatic analysis, we identified a protein known as signal-transducer-and-activator-of-transcription-1 (STAT-1) as a key regulator of disease and one that may serve as a therapeutic target. Moreover, we provided a novel therapeutic strategy to regulate exacerbation using a commercially available STAT-1 inhibitor, Fludarabine, that can potentially be used in clinical practice. Collectively, these studies provide a deep insight into the inflammation pathways underlying common viral infections and those that trigger asthma exacerbations. Further potential strategies for the treatment of asthma exacerbation are proposed.
- Subject
- asthma exacerbation; viral infection; immunolo-pathogenesis; influenza; rhinovirus; respiratory syncytial virus
- Identifier
- http://hdl.handle.net/1959.13/1509131
- Identifier
- uon:56214
- Rights
- Copyright 2022 Xiaoming Liu
- Language
- eng
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