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Infection and Immunity, December 2006, p. 6665-6674, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.00949-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Caveolin-1-Deficient Mice Show Defects in Innate Immunity and Inflammatory Immune Response during Salmonella enterica Serovar Typhimurium Infection{triangledown} ,{dagger}

Freddy A. Medina,1,2 Cecilia J. de Almeida,1,2 Elliott Dew,1,2 Jiangwei Li,1,2 Gloria Bonuccelli,1,2 Terence M. Williams,1,2 Alex W. Cohen,1,2 Richard G. Pestell,2 Philippe G. Frank,1,2 Herbert B. Tanowitz,3 and Michael P. Lisanti1,2,4*

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461,1 Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107,2 Departments of Pathology and Medicine, Albert Einstein College of Medicine, Bronx, New York 10461,3 Muscular and Neurodegenerative Disease Unit, University of Genova and G. Gaslini Pediatric Institute, Largo Gaslini 5, 16147 Genova, Italy4

Received 14 June 2006/ Returned for modification 23 July 2006/ Accepted 2 September 2006

A number of studies have shown an association of pathogens with caveolae. To this date, however, there are no studies showing a role for caveolin-1 in modulating immune responses against pathogens. Interestingly, expression of caveolin-1 has been shown to occur in a regulated manner in immune cells in response to lipopolysaccharide (LPS). Here, we sought to determine the role of caveolin-1 (Cav-1) expression in Salmonella pathogenesis. Cav-1–/– mice displayed a significant decrease in survival when challenged with Salmonella enterica serovar Typhimurium. Spleen and tissue burdens were significantly higher in Cav-1–/– mice. However, infection of Cav-1–/– macrophages with serovar Typhimurium did not result in differences in bacterial invasion. In addition, Cav-1–/– mice displayed increased production of inflammatory cytokines, chemokines, and nitric oxide. Regardless of this, Cav-1–/– mice were unable to control the systemic infection of Salmonella. The increased chemokine production in Cav-1–/– mice resulted in greater infiltration of neutrophils into granulomas but did not alter the number of granulomas present. This was accompanied by increased necrosis in the liver. However, Cav-1–/– macrophages displayed increased inflammatory responses and increased nitric oxide production in vitro in response to Salmonella LPS. These results show that caveolin-1 plays a key role in regulating anti-inflammatory responses in macrophages. Taken together, these data suggest that the increased production of toxic mediators from macrophages lacking caveolin-1 is likely to be responsible for the marked susceptibility of caveolin-1-deficient mice to S. enterica serovar Typhimurium.

* Corresponding author. Mailing address: Department of Cancer Biology, Kimmel Cancer Center, Bluemle Life Sciences Building, Room 933, 233 S. 10th Street, Philadelphia, PA 19107. Phone: (215) 503-9295. Fax: (215) 923-1098. E-mail: michael.lisanti{at}jefferson.edu.

{triangledown} Published ahead of print on 18 September 2006.

Editor: W. A. Petri, Jr.

{dagger} Supplemental material for this article can be found at http://iai.asm.org/.

Infection and Immunity, December 2006, p. 6665-6674, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.00949-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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