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Infection and Immunity, July 2008, p. 2913-2922, Vol. 76, No. 7
0019-9567/08/$08.00+0     doi:10.1128/IAI.01596-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Inositol Phosphatase SHIP Controls Salmonella enterica Serovar Typhimurium Infection In Vivo{triangledown}

Jennifer L. Bishop,1 Laura M. Sly,2 Gerald Krystal,2 and B. Brett Finlay1*

University of British Columbia, Michael Smith Laboratories, Room 301, 2185 East Mall, Vancouver, British Columbia V6T 1Z4, Canada,1 The Terry Fox Laboratory, British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada2

Received 3 December 2007/ Returned for modification 20 January 2008/ Accepted 8 April 2008

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. The 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 serovar 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 serovar Typhimurium in vivo. Cytokine analysis of serum from orally infected mice showed that ship–/– mice produce lower levels of Th1 cytokines than do ship+/+ animals at 2 days postinfection, 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 these data. M2 macrophages were the predominant population in vivo in both oral and intraperitoneal infections, since 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.

* Corresponding author. Mailing address: University of British Columbia, Michael Smith Laboratories, Room 301, 2185 East Mall, Vancouver, British Columbia V6T 1Z4, Canada. Phone: (604) 822-2210. Fax: (604) 822-9830. E-mail: bfinlay{at}interchange.ubc.ca

{triangledown} Published ahead of print on 21 April 2008.

Editor: A. J. Bäumler

Infection and Immunity, July 2008, p. 2913-2922, Vol. 76, No. 7
0019-9567/08/$08.00+0     doi:10.1128/IAI.01596-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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