feb18

February 18, 2005

The role of intestinal defensins in innate mucosal immunity

Nita H. Salzman
Department of Pediatrics, Division of Gastroenterology and the Department of Microbiology and Molecular Genetics, Medical College of Wisconsin

The gastrointestinal tract comprises the body's largest mucosal surface and is in constant contact with food, microbes, and other environmental antigens. The small intestine, because of its critical role in nutrient absorption, must be accessible to nutrients yet protected from harmful environmental stimuli and microbial infection. Unlike the large bowel and the bordering cecum, the small intestine normally shows low levels of bacterial colonization, and minimal evidence of inflammation, suggesting that there are highly effective non-inflammatory defenses of this mucosal surface. Antimicrobial peptides and proteins secreted by the mucosa comprise a portion of this defense. Defensins are gene-encoded endogenous antimicrobial peptides that are present in great abundance in Paneth cells, present at the bases of the small intestinal crypts. A focus of our laboratory is to understand the role of Paneth cell defensins in innate host defense. To do this, we developed a transgenic model system in which human defensin 5 is specifically expressed in mouse Paneth cells. Using this model, we are exploring the role of Paneth cell defensins in host response to pathogens and intestinal homeostasis.

References:

Zasloff, M. Antimicrobial peptides of multicellular organisms. Nature 415, 389-395 (2002).

Lehrer, R.I., Bevins, C.L. & Ganz, T. Defensins and other antimicrobial peptides. in Mucosal Immunology (eds. Ogra, P.L., Mestecky, J., Lamm, M.E., Strober, W.M. & Bienstock, J.) 89-99 (Academic Press, New York, 1998).

Salzman, N. H., D. Ghosh, K. Huttner, J. Russell, Y. Paterson, and C. Bevins. Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature 422:522-526 (2003) advance online publication, 19 March 2003 (doi:10.1038/nature01520).

Salzman, N. H., M. Chou, H. deJong, L. Liu, E.M. Porter, and Y. Paterson. Enteric Salmonella Infection Inhibits Paneth Cell Antimicrobial Peptide Expression. Infection and Immunity, 2003: 71(3): 1109-1115.

Salzman, N. H., H. de Jong, Y. Paterson, H. J. M. Harmsen, G. W. Welling and N. A. Bos. Analysis of 16S libraries of mouse gastrointestinal microflora reveals a large new group of mouse intestinal bacteria. Microbiology 2002; 148: 3651-3660

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