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Host-pathogen interaction mechanisms in Staphylococcus aureus infection

Wagner, Nelly (2017) Host-pathogen interaction mechanisms in Staphylococcus aureus infection. PhD thesis, University of Sheffield.

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Abstract

In spite of the availability of robust antibacterial strategies, Staphylococcus aureus still constitutes a major, global health threat. Indeed, it is responsible for a wide range of infections in both healthcare and community settings. Staphylococcal infections are difficult to treat due to antibiotic resistance and the action of a plethora of virulence factors that manipulate the host immune response. There is therefore a need to better understand the mechanisms of virulence of this bacterium, as well as the immune response of the host, in order to identify new therapeutic breakpoints. Mice and zebrafish systemic infection models have shown that S. aureus goes through an immune bottleneck, after which the pathogen clonally expands leading to abscess formation. Thus, only a few cells within the inoculum contribute directly to disease. Here, a zebrafish embryo model of systemic infection was used to characterise new aspects of host-pathogen interactions. My work examined the effect of antibiotic intervention on clonal expansion. Growth of pre-existing antibiotic resistant S. aureus is favoured over sensitive strains in the presence of sub-curative doses of antibiotics which do not apparently affect the antibiotic-sensitive population. This has important implications for the implementation of antibiotic treatment regimes. S. aureus disease models are characterised by the need for a large inoculum. Here it was demonstrated that attenuated mutants can substitute for much of the inoculum leading to death of the host. This shows that it is the number of organisms that is important for the initiation of infection, not that they are all pathogenic. The nature of the augmentation of virulence likely constitutes a specific immune interaction, as shown by whole-body level immune responses in the presence of S. aureus. The immune response to S. aureus is therefore a therapeutic target that could be exploited to enhance host survival.

Item Type: Thesis (PhD)
Keywords: Staphylococcus aureus Zebrafish Host-pathogen
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Identification Number/EthosID: uk.bl.ethos.713289
Depositing User: Ms Nelly Wagner
Date Deposited: 24 Apr 2017 11:16
Last Modified: 25 Sep 2019 20:02
URI: http://etheses.whiterose.ac.uk/id/eprint/16850

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