[{"key":"dc.contributor.author","value":"Bishop, Jennifer L.","language":null},{"key":"dc.date.accessioned","value":"2008-08-05T16:11:17Z","language":null},{"key":"dc.date.available","value":"2008-08-05T16:11:17Z","language":null},{"key":"dc.date.issued","value":"2008","language":null},{"key":"dc.identifier.uri","value":"http:\/\/hdl.handle.net\/2429\/1257","language":null},{"key":"dc.description.abstract","value":"The SH2 domain-containing inositol 5\u2019-phosphatase, SHIP, negatively regulates hematopoietic cell functions and is critical for maintaining immune homeostasis. However, whether SHIP plays a role in controlling bacterial infections in vivo remained unknown. Salmonella enterica causes human salmonellosis, a disease that ranges in severity from mild gastroenteritis to severe systemic illness, resulting in significant morbidity and mortality worldwide. The focus of this work was to determine the role of SHIP in a murine model of systemic Salmonellosis. Susceptibility of ship\u207a\/\u207aand ship\u207b\/\u207b mice to S. enterica serovar Typhimurium infection was compared. ship\u207b\/\u207b mice displayed an increased susceptibility to both oral and intraperitoneal S. Typhimurium infection and had significantly higher bacterial loads in intestinal and systemic sites than ship\u207a\/\u207amice, indicating a role for SHIP in the gut and systemic pathogenesis of S. Typhimurium in vivo. Blood cytokine levels showed that infected ship\u207b\/\u207b mice produce lower levels of Th1 polarizing cytokines compared to ship\u207a\/\u207a animals, and analysis of supernatants taken from M2 bone marrow derived macrophages correlated with this data. M2 macrophages were the predominant population in vivo during both oral and intraperitoneal infections. Because M2 macrophages are poor defenders against bacterial infection, these data suggest that M2 macrophage skewing in ship\u207b\/\u207b mice contributes to ineffective clearance of Salmonella.\nThe role of SHIP in the gut during enteric infections was also explored. ship\u207b\/\u207b mice were not susceptible to Citrobacter rodentium infection, yet developed severe inflammation of the ileum upon infection with this bacterium, with Salmonella, or when challenged orally with LPS. Increased collagen deposition was also observed at early time points post-infection, suggesting that ship\u207b\/\u207b mice may be used to study the development of inflammatory bowel diseases characterized by fibrosis, such as Crohn's.  \nBecause SHIP is such a critical negative regulator in both innate and adaptive immune cells, it has the potential to significantly alter the outcome of infections. This work highlights the fact that SHIP is important in vivo during Salmonellosis and opens new avenues to explore targeting SHIP in therapies for both systemic infections as well as inflammatory bowel diseases.","language":"en"},{"key":"dc.format.extent","value":"43544180 bytes","language":null},{"key":"dc.format.mimetype","value":"application\/pdf","language":null},{"key":"dc.language.iso","value":"eng","language":"en"},{"key":"dc.publisher","value":"University of British Columbia","language":null},{"key":"dc.rights","value":"Attribution-NonCommercial-NoDerivatives 4.0 International","language":null},{"key":"dc.rights.uri","value":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/","language":null},{"key":"dc.title","value":"The role of the inositol phosphatase, SHIP, in the innate immune response to Salmonella Typhimurium","language":"en"},{"key":"dc.type","value":"Text","language":null},{"key":"dc.degree.name","value":"Doctor of Philosophy - PhD","language":"en"},{"key":"dc.degree.discipline","value":"Microbiology and Immunology","language":"en"},{"key":"dc.degree.grantor","value":"University of British Columbia","language":null},{"key":"dc.date.graduation","value":"2008-11","language":"en"},{"key":"dc.type.text","value":"Thesis\/Dissertation","language":"en"},{"key":"dc.description.affiliation","value":"Science, Faculty of","language":null},{"key":"dc.description.affiliation","value":"Microbiology and Immunology, Department of","language":null},{"key":"dc.degree.campus","value":"UBCV","language":"en"},{"key":"dc.description.scholarlevel","value":"Graduate","language":"en"}]