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Lack of Functional P-Selectin Ligand Exacerbates Salmonella Serovar Typhimurium Infection¹

Winnie W. S. Kum^*, Sansan Lee^*, Guntram A. Grassl^*, Roza Bidshahri^*, Kimberly Hsu^*, Hermann J. Ziltener and B. Brett Finlay^2,*,

^* Michael Smith Laboratories, Biomedical Research Centre, and Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada

The selectin family of adhesion molecules mediates the recruitment of immune cells to the site of inflammation, which is critical for host survival of infection. To characterize the role of selectins in host defense against Salmonella Typhimurium infection, wild-type (WT) mice and mice lacking P-selectin glycoprotein ligand-1 (PSGL-1), P-, E-, or L-selectin, or the glycosyltransferase C2GlcNAcT-I (core 2) were infected using a Salmonella acute gastroenteritis model. Mice were monitored for survival and assessed for intestinal inflammation at 1 and 4 days postinfection. Infected mice lacking core 2, PSGL-1, or P-selectin showed a more pronounced morbidity and a significantly higher mortality rate associated with higher bacterial load and proinflammatory cytokine production, including that of TNF-, MCP-1, and IL-6, from the colons at 4 days postinfection as compared with WT control. Surprisingly, at 1 day postinfection, more severe inflammation and higher neutrophil infiltration were observed in the ceca of mice lacking core 2, PSGL-1, or P-selectin compared with WT control. Enhanced levels of ₄β₇⁺ and MAdCAM-1⁺ cells were observed in the ceca of infected mice lacking core 2, PSGL-1, or P-selectin. Neutrophil recruitment, cecal inflammation, and mortality rates were dramatically reduced in infected P-selectin knockout mice receiving blocking mAb to ₄β₇ integrin, indicating that this alternative adhesion molecule may attempt to compensate for the loss of selectins in neutrophil recruitment. These results demonstrate a definitive phenotypic abnormality in mice lacking core 2, PSGL-1, or P-selectin, suggesting that the interaction of functional PSGL-1 with P-selectin is an important process in host defense against Salmonella infection.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Genome British Columbia and Genome Prairie for the Pathogenomics of Innate Immunity Research Program and Canadian Institutes for Health Research (CIHR). G.A.G. was supported by postdoctoral fellowships from the Michael Smith Foundation for Health Research and the Deutsche Forschungsgemeinschaft. B.B.F. is a CIHR Distinguished Investigator, an Howard Hughes Medical Institute International Research Scholar, and the University of British Columbia Peter Wall Distinguished Professor.

² Address correspondence and reprint requests to Dr. B. Brett Finlay, University of British Columbia, Michael Smith Laboratories, Room 301, 2185 East Mall, Vancouver, British Columbia, V6T 1Z4 Canada. E-mail address: bfinlay{at}interchange.ubc.ca

³ Abbreviations used in this paper: PSGL, P-Selectin glycoprotein ligand; CBA, cytometric bead array; KO, knockout; MAdCAM, mucosal addressin cell adhesion molecule; MPO, myeloperoxidase; WT, wild type.