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The role of the inositol phosphatase, SHIP, in the innate immune response to Salmonella Typhimurium Bishop, Jennifer L.

Abstract

The SH2 domain-containing inositol 5’-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⁺/⁺and ship⁻/⁻ mice to S. enterica serovar Typhimurium infection was compared. ship⁻/⁻ 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⁺/⁺mice, indicating a role for SHIP in the gut and systemic pathogenesis of S. Typhimurium in vivo. Blood cytokine levels showed that infected ship⁻/⁻ mice produce lower levels of Th1 polarizing cytokines compared to ship⁺/⁺ 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⁻/⁻ mice contributes to ineffective clearance of Salmonella. The role of SHIP in the gut during enteric infections was also explored. ship⁻/⁻ 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⁻/⁻ mice may be used to study the development of inflammatory bowel diseases characterized by fibrosis, such as Crohn's. Because 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.

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