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Title: Regulation of hepatic inflammation and thrombosis during Salmonella infections
Author: Hitchcock, Jessica Ruth
ISNI:       0000 0004 5363 0145
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 2014
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Salmonella typhimurium is one of the most common causes of bacteraemia in children in sub-Saharan Africa and is prevalent in HIV-infected individuals. However, symptoms of this systemic infection are unclear, and while fatalities are frequent, how infection kills is unknown. Here we use a mouse model of systemic (but resolving) infection to investigate physiological and immunological aspects of the host response to infection. The liver is colonised during systemic infection, and in the model used, bacterial numbers peak at day 7 and are largely resolved within a month. Inflammatory lesions, consisting of multiple leukocyte populations, develop within the liver. These persist and are more severe once bacterial clearance is established. Whilst lesions can develop in the absence of T and B cells, these cells contribute to the regulation of inflammatory foci. In the absence of interferon-γ, lesions do not develop and inflammation in the liver is largely absent. In parallel, extensive platelet thrombosis occurs in the liver venous system and the shared kinetics with lesion formation suggest these phenotypes may be co-regulated. Here we describe how parenchymal and vascular inflammation are anchored by inflammatory up-regulation of podoplanin expression in the liver. Thrombosis is substantially abrogated in the absence of C-like lectin-type receptor-2 (CLEC-2) expression on platelets and we show that podoplanin (the physiological ligand for CLEC-2) expression on clodronate-sensitive myeloid populations is necessary for thrombus development. Therefore, the parallel association between inflammation and platelet activation could be the basis for developing novel treatments for systemic bacterial infections in humans.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QR180 Immunology ; RB Pathology