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

Paul Kelly

Mona Bajaj-Elliott

Max Katubulushi

Isaac Zulu

^{Centre for Adult and Paediatric Gastroenterology, Institute of Cell and Molecular Science, Barts & The London School of Medicine, London, UK}

^{University of Zambia School of Medicine, Lusaka, Zambia}

^{Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK}

^{Infectious Diseases and Microbiology, Institute of Child Health, London, UK}

^{Cancer Research UK, Lincoln's Inn, London, UK}

^{Department of Medical Microbiology and Immunology, University of California, Davis, USA}

Corresponding author: Dr Paul Kelly, Centre for Adult and Paediatric Gastroenterology, Institute of Cell and Molecular Science, Barts & The London School of Medicine, Queen Mary, University of London, Turner Street, London E1 2AD, UK Tel: +44 20 7882 7191; Fax: +44 20 7882 7192; email: ku.ca.lumq@yllek.p.m

Abstract

Background & Aims

The Paneth cell α-defensins HD5 and HD6 contribute to the antimicrobial barrier against intestinal infection. We have previously demonstrated that both HD5 and HD6 mRNA were reduced in adults living in urban Zambia compared to adults living in London. The aim of this study was to determine if α-defensin expression in Zambian adults is related to susceptibility to diarrhea during 3 years of follow-up.

Methods

We analyzed intestinal biopsies from a longitudinal cohort study in 83 Zambian adults using quantitative reverse transcription polymerase chain reaction (RT-PCR), Western blotting, immunohistochemistry and in situ hybridization, and we measured diarrhea incidence.

Results

HD5 and HD6 mRNA in Paneth cells varied between individuals, over time and seasonally, and was strongly correlated with mucosal architecture. Gene expression was restricted to Paneth cells. The median (interquartile range, IQR) HD5 mRNA was 6.0 (5.6-6.7) log₁₀ transcripts/μg total RNA in 18 participants who experienced diarrhea in two months after the biopsy was taken, compared to 6.8 (6.2-7.3) in 94 who did not (P=0.006), and a similar observation was made for HD6.

Conclusions

These data indicate that intestinal α-defensin expression is dynamic and seasonal, and suggest that susceptibility to intestinal infection is related to defensin expression.

Keywords: defensin, diarrhea, Africa, innate immunity, Paneth cell, incidence, enteropathy, HIV

Abstract

Footnotes

^{The authors do not have a commercial or other association that might pose a conflict of interest}

^{Financial support was obtained from The Wellcome Trust}

^{This work was presented at the Gordon conference on antimicrobial peptides, Ventura, CA, March 6-11, 2005 in poster form}

^{Corresponding author: Dr Paul Kelly, Tropical Gastroenterology & Nutrition group, Department of Medicine, University of Zambia School of Medicine, University Teaching Hospital, PO Box 531X, Ridgeway, Lusaka, Zambia, Tel and Fax: 00260 1 252269, email:}mz.tenreppoc@stug

Footnotes

REFERENCES

References

1. World Health Organisation . The World Health Report 2003: Global Health – today's challenges. Geneva: World Health Organization; 2003. [PubMed]
2. Gracey M. Diarrheal disease in perspective. In: Gracey M, Walker-Smith JA, editors. Diarrheal Disease. Vol. 38. Philadelphia: Vevey/Lippincott-Raven; 1997. pp. 1–12. (Nestle Nutrition Workshop Series). [PubMed]
3. Zulu I, Veitch A, Sianongo S, et al Albendazole chemotherapy for AIDS-related diarrhea in Zambia - clinical, parasitological and mucosal responses. Aliment Pharmacol Ther. 2002;16:595–601.[PubMed][Google Scholar]
4. Amadi B, Kelly P, Mwiya M, et al Intestinal and systemic infection, HIV, and mortality in Zambian children with persistent diarrhea and malnutrition. J Pediatr Gastroenterol Nutr. 2001;32:550–554.[PubMed][Google Scholar]
5. Boman HGPeptide antibiotics and their role in innate immunity. Annu Rev Immunol. 1995;13:61–92.[PubMed][Google Scholar]
6. Hancock RE, Diamond GThe role of cationic antimicrobial peptides in innate host defences. Trends Microbiol. 2000;8:402–410.[PubMed][Google Scholar]
7. Jones DE, Bevins CLPaneth cells of the human small intestine express an antimicrobial peptide gene. J Biol Chem. 1992;267:23216–23225.[PubMed][Google Scholar]
8. Jones DE, Bevins CLDefensin-6 mRNA in human Paneth cells: implications for antimicrobial peptides in host defense of the human bowel. FEBS Lett. 1993;315:187–192.[PubMed][Google Scholar]
9. Bevins CL, Martin-Porter E, Ganz TDefensins and innate host defense of the gastrointestinal tract. Gut. 1999;45:911–915.[Google Scholar]
10. Ganz TDefensins and host defense. Science. 1999;286:420–421.[PubMed][Google Scholar]
11. Porter EM, Bevins CL, Ghosh D, Ganz TThe multifaceted Paneth cell. Cell Mol Life Sci. 2002;59:156–170.[PubMed][Google Scholar]
12. Wilson CL, Ouellette AJ, Satchell DP, et al Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science. 1999;286:113–117.[PubMed][Google Scholar]
13. Salzman NH, Ghosh D, Huttner KM, Paterson Y, Bevins CLProtection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature. 2003;422:522–526.[PubMed][Google Scholar]
14. Dhaliwal W, Bajaj-Elliott M, Kelly PIntestinal defensin gene expression in human populations. Mol Immunol. 2003;40:469–475.[PubMed][Google Scholar]
15. Baker SJ, Mathan VITropical enteropathy and tropical sprue. Am J Clin Nutr. 1972;25:1047–1055.[PubMed][Google Scholar]
16. Lindenbaum J, Harmon JW, Gerson CDSubclinical malabsorption in developing countries. Am J Clin Nutr. 1972;25:1056–1061.[PubMed][Google Scholar]
17. Menzies IS, Zuckerman MJ, Nukajam WS, et al Geography of intestinal permeability and absorption. Gut. 1999;44:483–489.[Google Scholar]
18. Kelly P, Menzies I, Crane R, et al Responses of small intestinal architecture and function over time to environmental factors in a tropical population. Am J Trop Med Hyg. 2004;70:412–419.[PubMed][Google Scholar]
19. Veitch AM, Kelly P, Zulu IS, Segal I, Farthing MJTropical enteropathy: a T-cell-mediated crypt hyperplastic enteropathy. Eur J Gastroenterol Hepatol. 2001;13:1175–1181.[PubMed][Google Scholar]
20. Campbell DI, Murch SH, Elia M, et al Chronic T cell-mediated enteropathy in rural west African children: relationship with nutritional status and small bowel function. Pediatr Res. 2003;54:306–311.[PubMed][Google Scholar]
21. Savidge TC, Shmakov AN, Walker-Smith JA, Phillips ADEpithelial cell proliferation in childhood enteropathies. Gut. 1996;39:185–193.[Google Scholar]
22. Farthing MGJ. Acute diarrhea: pathophysiology. In: Gracey M, Walker-Smith JA, editors. Diarrheal Disease. Vol. 38. Philadelphia: Vevey/Lippincott-Raven; 1997. pp. 55–74. (Nestle Nutrition Workshop Series). [PubMed]
23. Guiraldes E, Hamilton JREffect of chronic malnutrition on intestinal structure, epithelial renewal, and enzymes in suckling rats. Pediatr Res. 1981;15:930–934.[PubMed][Google Scholar]
24. Kelly P, Zulu I, Amadi B, et al Morbidity and nutritional impairment in relation to CD4 count in a Zambian population with high HIV prevalence. Acta Trop. 2002;83:151–158.[PubMed][Google Scholar]
25. Central Statistical Office and ORC Macro . Zambia Demographic and Health Survey 2001 Final Report. Washington: ORC Macro; 2003. [PubMed]
26. Kelly P, Feakins R, Domizio P, et al Paneth cell granule depletion in the human small intestine under infective and nutritional stress. Clin Exp Immunol. 2004;135:303–309.[Google Scholar]
27. Ghosh D, Porter E, Shen B, et al Paneth cell trypsin is the processing enzyme for human defensin-5. Nat Immunol. 2002;3:583–590.[PubMed][Google Scholar]
28. Ericksen B, Wu Z, Lu W, Lehrer RIAntibacterial activity and specificity of the six human α-defensins. Antimicrob Ag Chemotherap. 2005;49:269–275.[Google Scholar]
29. Islam D, Bandholtz L, Nilsson J, et al Downregulation of bactericidal peptides in enteric infections: a novel immune escape mechanism with bacterial DNA as a potential regulator. Nat Med. 2001;7:180–185.[PubMed][Google Scholar]
30. Salzman NH, Chou MM, de Jong H, Liu L, Porter EM, Paterson YEnteric salmonella infection inhibits Paneth cell antimicrobial peptide expression. Infect Immun. 2003;71:1109–1115.[Google Scholar]

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

Abstract

Background &amp; Aims

Methods

Results

Conclusions

Footnotes

REFERENCES

References

Background & Aims