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Novel detection and evasion mechanisms pertinent to immunity against Salmonella Typhimurium

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cam.restrictionthesis_access_embargoed
cam.supervisorRandow, Felix
cam.thesis.fundingtrue
dc.contributor.authorAcklam, Frances
dc.date.accessioned2018-10-02T14:05:55Z
dc.date.available2018-10-02T14:05:55Z
dc.date.issued2018-10-20
dc.date.submitted2018-05-22
dc.date.updated2018-10-01T18:17:07Z
dc.description.abstractCells defend their cytosol against pathogen invasion using cell-autonomous immunity. When pathogens enter the cytosol they can damage host endomembranes, causing the mislocalisation of host molecules not normally found in the cytosol that are sensed as Danger Associated Molecular Patterns (DAMPs). Glycans exposed on damaged endomembranes are detected by danger receptors such as Galectin8. Galectin8 is recognised by the autophagy cargo receptor NDP52, specifically targeting the bacteria to autophagy. I hypothesised that other proteins would also be recruited to damaged endomembranes, which may initiate downstream mechanisms involved in cell-autonomous immunity or endomembrane repair. Identifying novel damage recruited proteins (DRPs) is difficult due to the short-lived and dynamic nature of damaged endomembranes. Therefore, I developed an unbiased approach for the identification of novel DRPs by proximity-dependent biotinylation using the ascorbate peroxidise enzyme APEX. This approach preferentially labels proteins located at damaged endomembranes for subsequent identification by TMT mass spectrometry. Four enriched proteins CCDC50, FBXO21, STAMBP and PDCD6 were identified as novel damage recruited proteins, recognising damaged SCVs. An alternative form of cell-autonomous immunity is the induction of cell death, for example by pyroptosis. Cell death destroys the bacteria’s replicative niche and exposes them to the extracellular space where they may be phagocytosed. I hypothesised that host cells might tag cytoplasmic bacteria with intracellular opsonins to assist in their phagocytosis following their release from host cells. However, my work revealed that intracellular Salmonella Typhimurium acquire phagocytosis protection, thus becoming internalised by phagocytes less efficiently than control bacteria. Phagocytosis protection was acquired rapidly after S.Typhimurium infection and was not observed with dead bacteria. Phagocytosis protection is only partially reversed by opsonisation in human serum. My results indicate that intracellular S.Typhimurium-induces an evasion mechanism to prevent its subsequent recognition by extracellular phagocytes.
dc.identifier.doi10.17863/CAM.30361
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/282996
dc.language.isoen
dc.publisher.collegeClare College
dc.publisher.departmentMRC Laboratory of Molecular Biology
dc.publisher.institutionUniversity of Cambridge
dc.rightsAll rights reserved
dc.rightsAll Rights Reserveden
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved/en
dc.subjectCell-autonomous Immunity
dc.subjectSalmonella
dc.subjectDanger receptors
dc.subjectPhagocytosis
dc.titleNovel detection and evasion mechanisms pertinent to immunity against Salmonella Typhimurium
dc.typeThesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.type.qualificationtitlePhD in Molecular Biology

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