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dc.contributor.advisorFitzgerald, Jonathanen
dc.contributor.advisorMorrison, Ivanen
dc.contributor.authorNutbeam-Tuffs, Stephen Williamen
dc.date.accessioned2017-11-16T14:02:15Z
dc.date.available2017-11-16T14:02:15Z
dc.date.issued2016-07-02
dc.identifier.urihttp://hdl.handle.net/1842/25519
dc.description.abstractBacterial superantigens (SAgs) are virulence factors that induce nonspecific T-cell proliferation contributing to host immune avoidance, and occasionally severe life-threatening toxinoses such as toxic shock syndrome. In the current study, the multiple functions of 3 superantigens named staphylococcal enterotoxin-like toxins X, Y and Z are investigated. SElX and SElZ were non-emetic in a musk shrew model of emesis. SElX is structurally and phylogenetically related to staphylococcal superantigen-like proteins (SSls) which are non-mitogenic but exhibit a variety of immune modulatory properties. We carried out protein and gene expression analysis of mutants of different S. aureus gene regulators and demonstrated that selx expression is controlled by saeRS, a two-component regulator linked to the bacterial response to phagocytic signals. Considering the co-regulation of SElX with known mediators of innate immune evasion we investigated a potential role for SElX in both humoral and cellular innate immune modulation and discovered that SElX strongly binds to human, bovine, murine, and laprine neutrophils and interferes with IgG-mediated phagocytosis, independently of Fcγ receptor signalling. Bacterial survival assays with neutrophils demonstrated that the deletion of selx significantly reduced the ability of S. aureus to resist neutrophil killing. Site-directed mutagenesis in the conserved sialic acid-binding motif of SElX abolished its neutrophil binding capacity, which is consistent with a critical role for glycosylated receptors in this interaction. Importantly, the sialic-acid binding mutants of SElX retained the ability to induce T-cell proliferation demonstrating that the distinct functions of SElX are mechanistically independent. Affinity precipitation experiments identified potential glycoprotein receptors for SElX and the interaction with protein ICAM-3, an important ligand for MAC-1 integrins, was validated suggesting SElX may interfere with cell signalling. Taken together, we present the first example of a bi-functional SAg that can manipulate two distinct arms of the human immune system and contribute to S. aureus survival during infection.en
dc.language.isoen
dc.publisherThe University of Edinburghen
dc.subjectstaphylococcal aureusen
dc.subjectS. aureusen
dc.subjectsuperantigenen
dc.subjectenterotoxinen
dc.titleFunctional characterisation of superantigens in Staphylococcus aureus disease pathogenesisen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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