- Title
- Immune mechanisms that underpin early-life Chlamydia respiratory infection-induced chronic lung disease
- Creator
- Starkey, Malcolm Ronald
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2014
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Asthma is a chronic allergic inflammatory condition of the airways that affects >300 million people worldwide. The inflammatory responses that induce asthmatic episodes, at least in allergic asthmatics, are driven predominantly through the actions of activated mast cells, eosinophils and type 2 T helper (Th2) lymphocytes. These activated inflammatory cells and the mediators they release promote inflammatory responses that damage the airways and result in structural changes in lung tissue, and mucus secreting cell (MSC) hyperplasia and metaplasia. The inflammatory response is accompanied by exaggerated sensitivity of the airways to non-specific stimuli, a phenomenon known as airway hyperresponsiveness (AHR). These pathological processes result in a narrowing of the airways leading to widespread airflow obstruction and breathing difficulties associated with asthma. Chlamydiae are atypical obligate intracellular bacteria that commonly cause asymptomatic infection and acute respiratory disease in human infants and adults. Chlamydia respiratory infections in early-life have been associated both clinically and experimentally with the development of reduced lung function and more severe asthma in later-life. Previous studies from our laboratory have shown that neonatal and infant, but not adult, Chlamydia respiratory infections in mice permanently alter the inflammatory phenotype and lung physiology to increase the severity of allergic airway disease (AAD) by increasing pulmonary interleukin-13 (IL-13) expression, mucus secreting cell (MSC) numbers and AHR. The aim of my PhD was to investigate the immune mechanisms that underpin these observations. The first study identified a novel role for tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in promoting Chlamydia respiratory infectioninduced pathology in in early life and subsequent chronic lung disease. Genetic deletion or inhibition of TRAIL using neutralising antibodies protected against neonatal Chlamydia respiratory infection-induced histopathology, inflammation and MSC hyperplasia, as well as subsequent alveolar enlargement and impaired lung function. The second study investigated the role of IL-13 in promoting early-life Chlamydia respiratory infection, infection-induced persistent AHR and severe AAD. IL-13-deficient mice had reduced infection, inflammation, MSC hyperplasia and AHR, which were restored by reconstitution of IL-13-deficient mice with exogenous IL-13. Surprisingly, infection of wild-type mice did not increase IL-13 production, but reduced IL-13 decoy receptor levels. Furthermore, neutralisation of IL-13 during infection prevented subsequent infection-induced severe AAD. The third study investigated the role of hematopoietic cells in driving early-life infection-induced severe AAD, using bone marrow chimera studies. Neonatal, infant and adult mice were infected with Chlamydia and nine weeks after infection bone marrow was collected and transferred into recipient irradiated naïve mice. AAD was induced eight weeks after adoptive transfer. Reconstitution of irradiated naïve mice with bone marrow from mice infected as neonates suppressed the hallmark features of AAD including IL-13 levels in the lung, MSC hyperplasia and AHR. In stark contrast, reconstitution with bone marrow from mice infected as infants increased the severity of AAD by increasing IL-13 levels, MSCs and AHR. Reconstitution with bone marrow from infected adult mice had no effects. Our novel findings indicate that neonatal and infant Chlamydia respiratory infections induce the development of chronic lung disease via distinct mechanisms at different ages. Our studies significantly contribute to understanding the association between early-life respiratory infections and the development of more severe asthma and may facilitate the development of more tailored treatments.
- Subject
- Chlamydia; asthma; emphysema; early-life infection; respiratory infection; Interleukin-13; TRAIL; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1042331
- Identifier
- uon:14037
- Rights
- Copyright 2014 Malcolm Ronald Starkey
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
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| View Details Download | ATTACHMENT02 | Thesis | 9 MB | Adobe Acrobat PDF | View Details Download |