- Title
- The role of rhinovirus and novel molecular mechanisms in allergic airways disease
- Creator
- Girkin, Jason Leslie Nicholas
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2017
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Rhinovirus (RV) infections are common ailments and are the most common precipitant of asthma exacerbations. This thesis contains investigations of novel mechanisms in RV infections and RV-induced exacerbations of house dust mite (HDM) driven allergic airways disease (AAD). The role of TLR7, CCL7, IRF-7, TRAIL and the off-target effect of long-acting β₂-agonists (LABAs) on PP2A are characterised in the host response to RV with a combination of in vivo and in vitro approaches. In chapter 2, TLR7 signalling is identified as crucial for antiviral responses to RV and for dampening allergic Th2 responses, protecting against RV-induced exacerbations of allergic airways disease. Likewise, high levels of allergic signalling through IL-5 suppresses TLR7 mediated antiviral responses. In chapter 3, results from the mouse lung transcriptome response to RV infection guided the investigation of two of the most up-regulated genes, CC-motif ligand 7 (CCL7) and interferon regulatory factor 7 (IRF-7). By inhibiting CCL7 or IRF-7 in naïve mice, the antiviral response and inflammation was suppressed following RV infection. Inhibiting CCL7 during infection of allergic mice also reduced inflammation. In chapter 3, tumour necrosis factor related apoptosis-inducing ligand (TRAIL) is shown to be pro-inflammatory and pro-viral during RV infection. TRAIL is up-regulated in the lung during the course of RV infection. TRAIL-deficient mice were protected against inflammation and airways hyperresponsiveness (AHR). RV-titre was reduced in TRAIL-deficient mice and manipulation of TRAIL in vitro had direct effects on viral titre. In chapter 4, the LABA Salmeterol demonstrated anti-inflammatory effects by directly activating PP2A, and suppressing AHR independently of β-2 adrenoreceptors. In summary, I have taken multiple approaches to identify novel mechanisms of the host response to RV infection and RV-induced exacerbations of allergic airways disease to identify novel therapeutic targets that may treat the underlying inflammatory mechanisms of asthma exacerbations.
- Subject
- rhinovirus; asthma; toll-like receptor 7; interferon regulatory factor 7; CC-motiff ligand 7; tumour necrosis factor-related apoptosis-inducing ligand; salmeterol; protein phosphatase 2a; animal models; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1335581
- Identifier
- uon:27454
- Rights
- Copyright 2017 Jason Leslie Nicholas Girkin
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 8 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 259 KB | Adobe Acrobat PDF | View Details Download |