Investigating the importance of the lung epithelium in response to Francisella tularensis

David, Jonathan (2012). Investigating the importance of the lung epithelium in response to Francisella tularensis. PhD thesis The Open University.



The role of immune cell populations in response to the intracellular pathogen Francisella tularensis has been well characterised. However, the host environment contains numerous cell-types capable of interacting with the bacteria to elicit a response. Multiplexed analyses, such as transcriptomics, enable the expression of entire host genomes to be investigated in order to identify novel aspects of host-pathogen interaction.

In this work, the murine lung transcriptome identifies the lung epithelium as an integral component of the host response to inhaled F. tularensis. The findings suggest that the maintenance of cell-cell junctions and extracellular matrix re-modelling are important factors in lung infection. In order to elucidate the mechanism of this epithelial response, further work, utilising a human pneumocyte cell line, A549, was performed in an advanced in vitro cell-culture system (rotating wall vessel bioreactors, RWVs). Characterisation of the RWV-cultured A549 cells indicated that this model system was more indicative of the in vivo environment than monolayer cells and is a suitable platform for the study of F. tularensis infection.

When infected with F. tularensis, the RWV-cultured A549 cells display increased resistance to infection than a standard monolayer model. The host mechanisms which result in this increased resistance were determined by transcriptional analysis. Several biological pathways were returned that may ultimately give rise to this resistant phenotype: complement activation, tight junction formation, extracellular matrix re-modelling and mucin production. To establish the mechanisms involved, inhibitor studies confirmed the importance of cell division control protein 42 (CDC42) in the endocytosis of F. tularensis by epithelial cells. Modulation of the host response successfully altered the severity of infection. These findings highlight the importance of the lung epithelium in vivo and in vitro and enable the hypothesis of several host mechanisms involved in the establishment of F. tularensis infection. The successful modulation of the host response confirms the potential importance of the lung epithelium in F. tularensis infection. Ultimately these findings may facilitate the design or discovery of therapeutics to decrease infection in the lung and help to combat F. tularensis in human hosts.

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