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1 Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA; Department of Biomedical Sciences, University of Missouri, Columbia, Missouri, USA
2 Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
3 Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, Ohio, USA
4 Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA; Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri, USA
5 Department of Pathology, University of California, Irvine, California, USA
6 Department of Pathology, University of California, Irvine, California, USA; Department of Microbiology and Molecular Genetics, University of California, Irvine, California, USA
7 Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri, USA
* To whom correspondence should be addressed. E-mail: clarkel{at}missouri.edu.
Paneth cells of intestinal crypts contribute to host defense by producing antimicrobial peptides that are packaged as granules for secretion into the crypt lumen. Here, we provide evidence using light and electron microscopy that post-secretory Paneth cell granules undergo limited dissolution and accumulate within the intestinal crypts of cystic fibrosis (CF) mice. Based on this finding, we evaluated bacterial colonization and expression of two major constituents of Paneth cells, i.e., alpha defensins (cryptdins) and lysozyme, in CF murine intestine. Paneth cell granules accumulated in intestinal crypt lumens in both untreated CF mice with impending intestinal obstruction and in CF mice treated with an osmotic laxative that prevented overt clinical symptoms and mucus accretion. Ultrastructure studies indicated little change in granule morphology within mucus casts, whereas granules in laxative-treated mice appear to undergo limited dissolution. Protein extracts from CF intestine had increased levels of processed cryptdins as compared to those from wild-type (WT) littermates. Nonetheless, colonization with aerobic bacteria species was not diminished in the CF intestine and oral challenge with a cryptdin-sensitive enteric pathogen, Salmonella typhimurium, resulted in greater colonization of the CF as compared to WT intestine. Modest down-regulation of cryptdin and lysozyme mRNA in CF intestine was shown by microarray analysis, real-time quantitative PCR and Northern blot analysis. Based upon these findings, we conclude that antimicrobial peptide activity in CF mouse intestine is compromised by inadequate dissolution of Paneth cell granules within the crypt lumens.
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