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Downregulation of bactericidal peptides in enteric infections: A novel immune escape mechanism with bacterial DNA as a potential regulator

Nature Medicine volume 7, pages 180–185 (2001)Cite this article

Abstract

Antibacterial peptides are active defense components of innate immunity. Several studies confirm their importance at epithelial surfaces as immediate barrier effectors in preventing infection. Here we report that early in Shigella spp. infections, expression of the antibacterial peptides LL-37 and human β-defensin-1 is reduced or turned off. The downregulation is detected in biopsies from patients with bacillary dysenteries and in Shigella- infected cell cultures of epithelial and monocyte origin. This downregulation of immediate defense effectors might promote bacterial adherence and invasion into host epithelium and could be an important virulence parameter. Analyses of bacterial molecules causing the downregulation indicate Shigella plasmid DNA as one mediator.

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Figure 1: Southern-blot analysis of RT-PCR reactions for three gene transcripts.
Figure 2: Immunoperoxidase staining of LL-37 in rectal biopsies during shigellosis using rabbit IgG antisera specific to LL-37 in combination with hematoxylin nuclear counter-staining.
Figure 3: Western-blot analysis with the LL-37 specific antisera on protein extract of biopsies.
Figure 4: RT-PCR and western-blot analyses of LL-37 expression in cell lines.
Figure 5: Expression of LL-37 affected by bacterial DNA.

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References

  1. Frohm, M. et al. The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders. J. Biol. Chem. 272, 15258–15263 (1997).

    Article  CAS  Google Scholar 

  2. Stolzenberg, E.D., Anderson, G.M., Ackermann, M.R., Whitlock, R.H. & Zasloff, M. Epithelial antibiotic induced in states of disease. Proc. Natl. Acad. Sci. USA 94, 8686–8690 (1997).

    Article  CAS  Google Scholar 

  3. Tarver, A.P. et al. Enteric β-defensin: molecular cloning and characterization of a gene with inducible intestinal epithelial cell expression associated with Cryptosporidium parvum infection. Infect. Immun. 66, 1045–1056 (1998).

    CAS  Google Scholar 

  4. Bals, R., Wang, X., Zasloff, M. & Wilson, J.M. The peptide antibiotic LL-37/hCAP-18 is expressed in epithelia of the human lung where it has broad antimicrobial activity at the airway surface. Proc. Natl. Acad. Sci. USA 95, 9541–9546 (1998).

    Article  CAS  Google Scholar 

  5. Agerberth, B. et al. Antibacterial components in bronchoalveolar lavage fluid from healthy individuals and sarcoidosis patients. Am. J. Respir. Crit. Care Med. 160, 283–290 (1999).

    Article  CAS  Google Scholar 

  6. Zhao, C., Wang, I. & Lehrer, R.I. Widespread expression of β-defensin hBD-1 in human secretory glands and epithelial cells. FEBS Lett. 396, 319–322 (1996).

    Article  CAS  Google Scholar 

  7. Harder, J., Bartels, J., Christophers, E. & Schroder, J.M. A peptide antibiotic from human skin. Nature 387, 861 (1997).

    Article  CAS  Google Scholar 

  8. Jones, D.E. & Bevins, C.L. Paneth cells of the human small intestine express an antimicrobial peptide gene. J. Biol. Chem. 267, 23216–23225 (1992).

    CAS  Google Scholar 

  9. Jones, D.E. & Bevins, C.L. Defensin-6 mRNA in human Paneth cells: implications for antimicrobial peptides in host defense of the human bowel. FEBS Lett. 315, 187–192 (1993).

    Article  CAS  Google Scholar 

  10. Bevins, C.L., Martin-Porter, E. & Ganz, T. Defensins and innate host defence of the gastrointestinal tract. Gut 45, 911–915 (1999).

    Article  CAS  Google Scholar 

  11. Boman, H.G. Antibacterial peptides: key components needed in immunity. Cell 65, 205–207 (1991).

    Article  CAS  Google Scholar 

  12. O'Neil, D.A. et al. Expression and regulation of the human β-defensins hBD-1 and hBD-2 in intestinal epithelium. J. Immunol. 163, 6718–6724 (1999).

    CAS  Google Scholar 

  13. O'Neil, D.A. et al. Regulation of human β-defensins by gastric epithelial cells in response to infection with helicobacter pylori or stimulation with interleukin-1. Infect. Immun. 68, 5412–5415 (2000).

    Article  CAS  Google Scholar 

  14. Dorman, C.J. & Porter, M.E. The Shigella virulence gene regulatory cascade: a paradigm of bacterial gene control mechanisms. Mol. Microbiol. 29, 677–684 (1998).

    Article  CAS  Google Scholar 

  15. Menard, R., Dehio, C. & Sansonetti, P.J. Bacterial entry into epithelial cells: the paradigm of Shigella. Trends Microbiol. 4, 220–226 (1996).

    Article  CAS  Google Scholar 

  16. Zychlinsky, A. & Sansonetti, P.J. Apoptosis as a proinflammatory event: what can we learn from bacteria- induced cell death? Trends Microbiol. 5, 201–204 (1997).

    Article  CAS  Google Scholar 

  17. Sorensen, O., Cowland, J.B., Askaa, J. & Borregaard, N. An ELISA for hCAP-18, the cathelicidin present in human neutrophils and plasma. J. Immunol. Methods 206, 53–59 (1997).

    Article  CAS  Google Scholar 

  18. Sansonetti, P.J. Molecular and cellular mechanisms of invasion of the intestinal barrier by enteric pathogens. The paradigm of Shigella. Folia Microbiol. 43, 239–246 (1998).

    Article  CAS  Google Scholar 

  19. Agerberth, B. et al. The human antimicrobial and chemotactic peptides LL-37 and α-defensins are expressed by specific lymphocyte and monocyte populations. Blood 96, 3086–3093 (2000).

    CAS  Google Scholar 

  20. Kagnoff, M.F. & Eckmann, L. Epithelial cells as sensors for microbial infection. J. Clin. Invest. 100, 6–10 (1997).

    Article  CAS  Google Scholar 

  21. Bliska, J.B., Galan, J.E. & Falkow, S. Signal transduction in the mammalian cell during bacterial attachment and entry. Cell 73, 903–920 (1993).

    Article  CAS  Google Scholar 

  22. Siebers, A. & Finlay, B.B. Models to study enteropathogenic bacteria: lessons learned from Shigella. Trends Microbiol. 3, 207–209 (1995).

    Article  CAS  Google Scholar 

  23. Albert, M.J., Faruque, A.S., Faruque, S.M., Sack, R.B. & Mahalanabis, D. Case-control study of enteropathogens associated with childhood diarrhea in Dhaka, Bangladesh. J. Clin. Microbiol. 37, 3458–3464 (1999).

    CAS  Google Scholar 

  24. Islam, D., Wretlind, B., Ryd, M., Lindberg, A.A. & Christensson, B. Immunoglobulin subclass distribution and dynamics of Shigella-specific antibody responses in serum and stool samples in shigellosis. Infect. Immun. 63, 2054–2061 (1995).

    CAS  Google Scholar 

  25. Raqib, R. et al. Persistence of local cytokine production in shigellosis in acute and convalescent stages. Infect. Immun. 63, 289–296 (1995).

    CAS  Google Scholar 

  26. Islam, D., Veress, B., Bardhan, P.K., Lindberg, A.A. & Christensson, B. In situ characterization of inflammatory responses in the rectal mucosae of patients with shigellosis. Infect. Immun. 65, 739–749 (1997).

    CAS  Google Scholar 

  27. Islam, D., Veress, B., Bardhan, P.K., Lindberg, A.A. & Christensson, B. Quantitative assessment of IgG and IgA subclass producing cells in rectal mucosa during shigellosis. J. Clin. Pathol. 50, 513–520 (1997).

    Article  CAS  Google Scholar 

  28. Mandic-Mulec, I., Weiss, J. & Zychlinsky, A. Shigella flexneri is trapped in polymorphonuclear leukocyte vacuoles and efficiently killed. Infect. Immun. 65, 110–115 (1997).

    CAS  Google Scholar 

  29. Shafer, W.M., Qu, X., Waring, A.J. & Lehrer, R.I. Modulation of Neisseria gonorrhoeae susceptibility to vertebrate antibacterial peptides due to a member of the resistance/nodulation/division efflux pump family. Proc. Natl. Acad. Sci. USA 95, 1829–1833 (1998).

    Article  CAS  Google Scholar 

  30. Guo, L. et al. Lipid A acylation and bacterial resistance against vertebrate antimicrobial peptides. Cell 95, 189–198 (1998).

    Article  CAS  Google Scholar 

  31. Krieg, A.M. The role of CpG motifs in innate immunity. Curr. Opin. Immunol. 12, 35–43 (2000).

    Article  CAS  Google Scholar 

  32. Wagner, H. Bacterial CpG DNA activates immune cells to signal infectious danger. Adv. Immunol. 73, 329–368 (1999).

    Article  CAS  Google Scholar 

  33. Chu, R.S. et al. CpG oligodeoxynucleotides downregulate macrophage class II MHC antigen processing. J. Immunol. 163, 1188–1194 (1999).

    CAS  Google Scholar 

  34. Gudmundsson, G.H. et al. The human gene FALL39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes. Eur. J. Biochem. 238, 325–332 (1996).

    Article  CAS  Google Scholar 

  35. Larrick, J.W. et al. Human CAP18: a novel antimicrobial lipopolysaccharide-binding protein. Infect. Immun. 63, 1291–1297 (1995).

    CAS  Google Scholar 

  36. Cowland, J.B., Johnsen, A.H. & Borregaard, N. hCAP-18, a cathelin/pro-bactenecin-like protein of human neutrophil specific granules. FEBS Lett. 368, 173–176 (1995).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the participants in the study; N.H. Alam for help with biopsy samples; G. Ara and Sharifunnahar for technical assistance; Masuda and Momtaz for assistance in recruiting patients and control subjects; E. Ólafsson for help with statistical analysis; K. Nilsson for the gift of the U937 cell-line; R.A. Harris for linguistic advice; and B. Axelsson for technical assistance. This study was supported by grants from Swedish Agency for Research Co-operation with Developing Countries (SAREC), Centre for Diarrhoeal Disease Research, Bangladesh, the Swedish Medical Research Council, The Swedish Foundation for Strategic Research, the Swedish Cancer Society, Magnus Bergvall's Foundation, Åke Wiberg's Foundation, Ruth and Richard Julin's Foundation and Prof. Nanna Svartz' Foundation.

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Authors and Affiliations

  1. Laboratory Sciences Division, International Center for Diarrhoeal Disease Research, 1000 Dhaka, Bangladesh

    Dilara Islam

  2. Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, S-171 77, Sweden

    Lisa Bandholtz, Hans Wigzell & Gudmundur H. Gudmundsson

  3. Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, S-171 77, Sweden

    Birgitta Agerberth

  4. Department of Medicine, Huddinge Hospital, Huddinge, S-141 86, Sweden

    Jakob Nilsson

  5. Department of Immunology, Microbiology and Pathology, Huddinge Hospital, Huddinge, S-141 86, Sweden

    Birger Christensson

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  1. Dilara Islam
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Correspondence to Gudmundur H. Gudmundsson.

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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 7, 180–185 (2001). https://doi.org/10.1038/84627

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