The inositol phosphatase SHIP controls Salmonella Typhimurium infection in vivo

University of British Columbia, Michael Smith Laboratories, Room 301, 2185 East Mall, Vancouver, British Columbia, Canada, V6T 1Z4; The Terry Fox Laboratory, British Columbia Cancer Research Centre, 675 West 10^th Avenue, Vancouver, British Columbia, Canada, V5Z 1L3

^* To whom correspondence should be addressed. Email: bfinlay{at}interchange.ubc.ca.

	Abstract

The SH2 domain-containing inositol 5'-phosphatase, SHIP, negatively regulates various hematopoietic cell functions and is critical for maintaining immune homeostasis. However, whether SHIP plays a role in controlling bacterial infections in vivo remains 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. Susceptibility of ship^+/+ and ship^-/- mice and bone marrow-derived macrophages 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 associated and systemic pathogenesis of S. Typhimurium in vivo. Cytokine analysis of serum from orally infected mice showed that ship^-/- mice produce lower levels of Th1 cytokines compared to ship^+/+ animals at two days post-infection, and in vitro analysis of supernatants taken from infected bone marrow-derived macrophages derived to mimic the in vivo ship^-/- alternatively activated (M2) macrophage phenotype correlated with this data. M2 macrophages were the predominant population in vivo in both oral and intraperitoneal infections, as tissue macrophages within the small intestine and peritoneal macrophages from ship^-/- mice showed elevated levels of the M2 macrophage markers Ym1 and Arginase 1 compared to ship^+/+ cells. Based on these data, we propose that M2 macrophage skewing in ship^-/- mice contributes to ineffective clearance of Salmonella in vivo.