- Title
- Mechanisms of predisposition to secondary bacterial pneumonia
- Creator
- Brown, Alexandra Cerelina
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2017
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Bacterial pneumonia is one of the most common infectious diseases globally. There are several pre-existing diseases that increase the risk of contracting secondary bacterial pneumonia. Respiratory viral infections and chronic obstructive pulmonary disease (COPD) are two of the most common and clinically relevant diseases that increase the risk of secondary bacterial pneumonia. Importantly, preventative strategies such as vaccines do not have complete efficacy and bacterial pathogens are increasingly becoming resistant to antibiotics. Increasing our understanding of the mechanisms of susceptibility to secondary bacterial pneumonia may identify targets and the potential for the development of new therapeutics for their prevention and treatment. Recent studies have demonstrated that viral infections and COPD dysregulate a range of different immune response that are important in defence against bacterial infections. Identifying whether there are commonly dysregulated immune responses caused by these predisposing diseases states may prove useful in the development of new therapeutics for secondary bacterial pneumonia. My thesis studies has utilised mouse models of pneumonia virus of mice (PVM) infection, influenza A virus (IAV) infection and cigarette smoke induced-COPD followed by secondary Streptococcus pneumoniae infection to investigate the mechanisms that lead to secondary bacterial pneumonia. Immune responses during secondary bacterial infection were analysed by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Although, several immune responses in these models differed, I observed a common increase in the number of programmed death-1 (PD-1) expressing cells during secondary S. pneumoniae infection. The PD-1/PD-L pathway is widely immunologically expressed and capable of suppressing the function of both innate and adaptive immune cells that are important in defence against bacterial infections. Increases in this pathway are therefore a potential mechanism of increased susceptibility. Interestingly, PD-1 expressing cell types differed between models of S. pneumoniae infection secondary to viral infection and COPD. Prior viral infections primarily increased the number of PD-1 expressing CD8+ T-cells, whilst COPD primarily increased PD-1 expressing macrophages. I then went on to demonstrate that blocking PD-1 signalling during PVM or IAV infection reduced the peak of secondary S. pneumoniae infection, which was dependent on the presence of CD8+ T-cells. Furthermore, blocking PD-1 signalling on macrophages treated with cigarette smoke extract restored their bacterial killing capacity. These findings have furthered our understanding of immune responses that induce susceptibility to bacterial pneumonia during viral infection and COPD, and suggest a potential role for the PD-1/PD-L pathway, which may act through different mechanisms. Importantly, these studies have also highlighted the PD-1/PD-L pathway as a potential target for development of new therapeutics for secondary bacterial pneumonia for at risk populations.
- Subject
- bacterial pneumonia; respiratory viral infections; COPD
- Identifier
- http://hdl.handle.net/1959.13/1333532
- Identifier
- uon:27102
- Rights
- Copyright 2017 Alexandra Cerelina Brown
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 2 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 100 KB | Adobe Acrobat PDF | View Details Download |