- Title
- Investigating the mechanisms that underpin early-life Chlamydia respiratory infection-induced chronic lung disease using a neonatal C. muridarum mouse model
- Creator
- Nguyen, Duc Hoai
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2019
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Asthma is a chronic inflammatory disease that affects up to 300 million people worldwide. The disease is driven by aberrant immune responses to non-specific stimuli, which is characterised by the activation of mast cells, eosinophils and type 2 T helper (TH2) cells. These immune cells release mediators which cause injury to the airway mucosa and surrounding tissues and result in mucosal swelling, mucous secreting cell hyperplasia and metaplasia and oedema. These responses are accompanied by exaggerated sensitivity of the airways to non-specific stimuli, a phenomenon known as airway hyperresponsiveness (AHR). Together, these responses results in a narrowing of the airways leading to wheezing, widespread airflow obstruction and breathing difficulties associated with asthma. Chlamydia is an obligate intracellular bacterial pathogen that is a common cause of respiratory infection in infants and adults. There is substantial evidence from both clinical and experimental studies that identify an association between Chlamydia respiratory infection in early life and the development of chronic lung disease in later life. Previous experimental studies from our group showed that neonatal and infant but not adult Chlamydia respiratory infection results in increased AHR in later life, with neonatal Chlamydia respiratory infection also resulting in permanent emphysema-like alveolar enlargement. In the background of these studies, the aim of the studies described in this thesis were to profile the immune responses underlying these observations, to identify the physiological mechanisms underlying early-life infection-induced AHR and to investigate several potential therapies for the long-term deleterious consequences of early life respiratory infection. In Chapter 2, we identify the role of the TLR2 and the IL-13 signalling pathways in the development of Chlamydia-induced AHR. Activation of the TLR2 signalling pathway led to the activation of the IL-13 signalling pathway and the up-regulation of miR-21. Genetic deletion of either TLR2 or IL-13 as well as inhibiting miR-21 expression protected mice against Chlamydia infection-induced AHR. In Chapter 3, we demonstrate that small airways have little contribution to the development of infection-induced AHR. Early-life Chlamydia infection increased collagen deposition around the small airways, but had no effect on small airway smooth muscle thickness or small airway epithelial layer tight junction factors. Finally, early-life Chlamydia infection had no effect on small airway contractility. In Chapter 4, we investigated the effect of targeting two signalling pathways: PI3K and PP2A signalling pathways and two potential treatments: dexamethasone and antibiotics. We first demonstrate that treatment with antibiotics during infection protected mice against infection-induced AHR, but promoted persistent AHR in non-infected mice. We then demonstrate that targeting either the PI3K signalling pathway or the PP2A signalling pathway had no effect on the infection-induced AHR. Finally, we showed that dexamethasone treatment protected mice against infection-induced AHR but had no effect on ovalbumin (Ova)-sensitised infection-induced allergic airway disease (AAD).
- Subject
- asthma; chlamydia; early-life infection
- Identifier
- http://hdl.handle.net/1959.13/1408606
- Identifier
- uon:35862
- Rights
- Copyright 2019 Duc Hoai Nguyen
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 5 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 155 KB | Adobe Acrobat PDF | View Details Download |