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. 2006 May 15;193(10):1464-70.
doi: 10.1086/503747. Epub 2006 Apr 12.

Reduced gene expression of intestinal alpha-defensins predicts diarrhea in a cohort of African adults

Paul Kelly  1 , Mona Bajaj-Elliott, Max Katubulushi, Isaac Zulu, Richard Poulsom, Roger A Feldman, Charles L Bevins, Winnie Dhaliwal
Affiliations

Reduced gene expression of intestinal alpha-defensins predicts diarrhea in a cohort of African adults

Paul Kelly et al. J Infect Dis. .

Abstract

Background: Human defensin (HD) 5 and HD6, both Paneth cell alpha-defensins, contribute to the antimicrobial barrier against intestinal infection. We have previously demonstrated that levels of both HD5 and HD6 mRNA were reduced in adults living in urban Zambia, compared with those in adults living in London. The aim of the present study was to determine, during 2 years of follow-up, whether alpha-defensin expression in Zambian adults is related to susceptibility to diarrhea.

Methods: We analyzed intestinal biopsy samples from a longitudinal cohort study conducted in 83 Zambian adults by quantitative reverse-transcription polymerase chain reaction, Western blotting, immunohistochemistry, and in situ hybridization, and we measured the incidence of diarrhea.

Results: Levels of HD5 and HD6 mRNA in Paneth cells varied between participants, over time, and seasonally and were strongly correlated with mucosal architecture. Gene expression was almost exclusively restricted to Paneth cells. The median (interquartile range) HD5 mRNA level was 6.0 (5.6-6.7) log10 transcripts/microg of total RNA among 18 participants who experienced diarrhea within 2 months after biopsy-sample collection, compared with 6.8 (6.2-7.3) log10 transcripts/microg of total RNA among 94 participants who did not (P=.006). A similar observation was made for HD6.

Conclusions: These data indicate that intestinal alpha-defensin expression is dynamic and seasonal and suggest that susceptibility to intestinal infection is related to alpha-defensin expression.

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Figures

Figure 1
Figure 1
Longitudinal changes in HD5 (solid line) and HD6 (dashed line) mRNA at 3 time points over 2 years. Data from twelve participants from the Lusaka population have been selected to demonstrate the range of variation seen. mRNA is shown as log10 transcripts/μg total RNA.
Figure 2
Figure 2
A​ In situ hybridization using antisense riboprobe to HD5. B Immunostaining using monoclonal anti-HD5 antibody. C​ In situ hybridization using antisense riboprobe to HD6. Labelling of mRNA and peptide was almost exclusively localized to the Paneth cell compartment.
Figure 3
Figure 3
Western blot of tissue extracts of jejunal biopsies probed with anti-HD5 antibody. Gel electrophoresis was performed by acid-urea polyacrylamide gel electrophoresis in which peptides are separated by both size and charge. Recombinant peptides are therefore used as markers of migration. Lane 1, recombinant pro-HD5 (20-94); lane 2, recombinant HD5; lanes 3-7, individual biopsies; lane 8, control ileal tissue from healthy patient. The quantity and isoform distribution of propeptide shows little variation. The diffuse, slow migrating band above the pro-HD5 control corresponds to an O-linked glycan modification of the HD5 (20-94) propeptide (C. L. Bevins, unpublished data).
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