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Infect Immun, March 1998, p. 1045-1056, Vol. 66, No. 3
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Enteric beta -Defensin: Molecular Cloning and Characterization of a Gene with Inducible Intestinal Epithelial Cell Expression Associated with Cryptosporidium parvum Infection

Alan P. Tarver,1 Douglas P. Clark,2,dagger Gill Diamond,1,Dagger John P. Russell,1 Hediye Erdjument-Bromage,3 Paul Tempst,3 Kenneth S. Cohen,1 Douglas E. Jones,2 Ray W. Sweeney,2 Mary Wines,1 Shirley Hwang,1 and Charles L. Bevins1,4,*

Division of Human Genetics and Molecular Biology, The Children's Hospital of Philadelphia, and Departments of Pediatrics1 and Pathology,2 University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; Memorial Sloan-Kettering Cancer Center, New York, New York 100213; and Department of Immunology, Gastroenterology and Colorectal Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio 441954

Received 21 August 1997/Returned for modification 21 November 1997/Accepted 10 December 1997

A growing body of evidence suggests that endogenous antibiotics contribute to the innate defense of mammalian mucosal surfaces. In the cow, beta -defensins constitute a large family of antibiotic peptides whose members have been previously isolated from the respiratory and oral mucosa, as well as circulating phagocytic cells. A novel bovine genomic clone with sequence related to those of these alpha -defensins was isolated and characterized. The corresponding cDNA was isolated from a small intestinal library; its open reading frame predicts a deduced sequence of a novel beta -defensin, which we designate enteric beta -defensin (EBD). Northern blot analysis of a variety of bovine tissues revealed that EBD mRNA is highly expressed in the distal small intestine and colon, anatomic locations distinct from those for previously characterized beta -defensins. EBD mRNA was further localized by in situ hybridization to epithelial cells of the colon and small intestinal crypts. Infection of two calves with the intestinal parasite Cryptosporidium parvum induced 5- and 10-fold increases above control levels of EBD mRNA in intestinal tissues. An anchored-PCR strategy was used to identify other beta -defensin mRNAs expressed in the intestine. In addition to that of EBD, several low-abundance cDNAs which corresponded to other beta -defensin mRNAs were cloned. Most of these clones encoded previously characterized beta -defensins or closely related isoforms, but two encoded a previously uncharacterized prepro-beta -defensin. Northern blot evidence supported that all of these other beta -defensin genes are expressed at levels lower than that of the EBD gene in enteric tissue. Furthermore, some of these beta -defensin mRNAs were abundant in bone marrow, suggesting that in enteric tissue their expression may be in cells of hematopoietic origin. Extracts of small intestinal mucosa obtained from healthy cows have numerous active chromatographic fractions as determined by an antibacterial assay, and one peptide was partially purified. The peptide corresponded to one of the low-abundance cDNAs. This study provides evidence of beta -defensin expression in enteric tissue and that the mRNA encoding a major beta -defensin of enteric tissue, EBD, is inducibly expressed in enteric epithelial cells. These findings support the proposal that beta -defensins may contribute to host defense of enteric mucosa.

* Corresponding author. Mailing address: Department of Immunology, NN 10, The Cleveland Clinic Foundation Research Institute, 9500 Euclid Ave., Cleveland, OH 44195. Phone: (216) 444-9107. Fax: (216) 444-9329. E-mail: bevinsc{at}cesmtp.ccf.org.

dagger Present address: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287-6940.

Dagger Present address: Department of Anatomy, Cell Biology and Injury Sciences, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103. 




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