- Title
- Mechanism of infection of bronchial epithelial cells by human and avian influenza viruses
- Creator
- Hsu, Alan (Chen-Yu)
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2010
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Respiratory epithelial cells including bronchial epithelial cells (BECs) are the initial site of infection with influenza viruses, and the anti-viral responses elicited by these cells are a critical first line of defense against respiratory viral infection and can induce effective adaptive immune responses. However, relatively little is known about the importance of this innate anti-viral response, and the magnitude and effectiveness of this response is poorly understood. In addition to human influenza, avian influenza viruses are a potential source of future pandemics, therefore it is also critical to examine the effectiveness of the host anti-viral system to low and high pathogenic avian influenza viruses. Anti-viral responses to a human influenza H3N2, a low pathogenic avian influenza H11N9 and a high pathogenic avian influenza H5N1 was profiled using Calu-3 cells and primary bronchial epithelial cells (pBECs) to model proximal airway cells and A549 cells to reflect alveolar cells. The susceptibility of BECs to influenza infection was not solely dependent on the sialic acid-bearing glycoprotein expression and was affected by the apoptosis and anti-viral responses after infection. The earlier and greater anti-viral signaling and protein production correlated with the control of infection. However the H3N2 strain resulted in a delay in anti-viral signaling and impaired release of type I and type III interferons (IFNs) compared to the H11N9 virus. The differences in anti-viral induction between H3N2 and H11N9 were partly due to the influenza non-structural (NS) 1 protein. The gene encoding for NS1 was transfected into the BECs and the H3N2 NS1 induced a greater inhibition of anti-viral responses compared to the H11N9 NS1. Regardless of this inhibition by the influenza viruses, the constitutive secretion of IFN-β by BECs played a more critical role in inducing late anti-viral signaling via type I IFN receptors and was crucial in limiting viral infection by apoptosis. Infection with H5N1 resulted in a complete abolishment of this response in the infected BECs, including those induced by the constitutive IFN-β. This was due to the robust inhibition of host anti-viral responses by the NS1 protein of H5N1. This study characterizes anti-influenza virus responses in airway epithelial cells and shows for the first time that constitutive IFN-β release plays an important role in initiating protective late IFN-stimulated responses during influenza infection in airway epithelial cells. In addition, the subversion of human anti-viral responses may be an important requirement for influenza viruses to adapt to the human host and induce disease. Furthermore by understanding both of these avenues will identify targets for potential therapeutics.
- Subject
- influenza; innate immunity; bronchial epithelial cells
- Identifier
- http://hdl.handle.net/1959.13/917312
- Identifier
- uon:8266
- Rights
- Copyright 2010 Alan (Chen-Yu) Hsu
- Language
- eng
- Full Text
- Hits: 593
- Visitors: 1165
- Downloads: 299
| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Abstract | 186 KB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Thesis | 11 MB | Adobe Acrobat PDF | View Details Download |