Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits

Nature volume 455, pages 804–807 (2008)Cite this article

Abstract

Infection with antibiotic-resistant bacteria, such as vancomycin-resistant Enterococcus (VRE), is a dangerous and costly complication of broad-spectrum antibiotic therapy1,2. How antibiotic-mediated elimination of commensal bacteria promotes infection by antibiotic-resistant bacteria is a fertile area for speculation with few defined mechanisms. Here we demonstrate that antibiotic treatment of mice notably downregulates intestinal expression of RegIIIγ (also known as Reg3g), a secreted C-type lectin that kills Gram-positive bacteria, including VRE. Downregulation of RegIIIγ markedly decreases in vivo killing of VRE in the intestine of antibiotic-treated mice. Stimulation of intestinal Toll-like receptor 4 by oral administration of lipopolysaccharide re-induces RegIIIγ, thereby boosting innate immune resistance of antibiotic-treated mice against VRE. Compromised mucosal innate immune defence, as induced by broad-spectrum antibiotic therapy, can be corrected by selectively stimulating mucosal epithelial Toll-like receptors, providing a potential therapeutic approach to reduce colonization and infection by antibiotic-resistant microbes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: MyD88-mediated signalling in non-haematopoietic cells is required for RegIIIγ-mediated clearance of VRE.
Figure 2: RegIIIγ expression is downregulated in antibiotic-treated mice, correlating with decreased clearance of VRE.
Figure 3: Administration of LPS to antibiotic-treated mice restores RegIIIγ levels and enhances luminal VRE killing.
Figure 4: Delayed LPS treatment of mice receiving antibiotics restores RegIIIγ levels and enhances luminal VRE killing.

Similar content being viewed by others

References

  1. Rice, L. B. Emergence of vancomycin-resistant enterococci. Emerg. Infect. Dis. 7, 183–187 (2001)

    Article  CAS  Google Scholar 

  2. Rice, L. B. Antimicrobial resistance in gram-positive bacteria. Am. J. Infect. Control 34, S11–S19 (2006)

    Article  Google Scholar 

  3. Murray, B. E. Vancomycin-resistant enterococcal infections. N. Engl. J. Med. 342, 710–721 (2000)

    Article  CAS  Google Scholar 

  4. Richards, M. J., Edwards, J. R., Culver, D. H. & Gaynes, R. P. Nosocomial infections in combined medical-surgical intensive care units in the United States. Infect. Control Hosp. Epidemiol. 21, 510–515 (2000)

    Article  CAS  Google Scholar 

  5. Wenzel, R. P. & Edmond, M. B. Managing antibiotic resistance. N. Engl. J. Med. 343, 1961–1963 (2000)

    Article  CAS  Google Scholar 

  6. Donskey, C. J. The role of the intestinal tract as a reservoir and source for transmission of nosocomial pathogens. Clin. Infect. Dis. 39, 219–226 (2004)

    Article  Google Scholar 

  7. Cash, H. L., Whitham, C. V., Behrendt, C. L. & Hooper, L. V. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313, 1126–1130 (2006)

    Article  ADS  CAS  Google Scholar 

  8. Hooper, L. V., Stappenbeck, T. S., Hong, C. V. & Gordon, J. I. Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nature Immunol. 4, 269–273 (2003)

    Article  CAS  Google Scholar 

  9. Brandl, K., Plitas, G., Schnabl, B., DeMatteo, R. P. & Pamer, E. G. MyD88-mediated signals induce the bactericidal lectin RegIII gamma and protect mice against intestinal Listeria monocytogenes infection. J. Exp. Med. 204, 1891–1900 (2007)

    Article  CAS  Google Scholar 

  10. Cash, H. L., Whitham, C. V. & Hooper, L. V. Refolding, purification, and characterization of human and murine RegIII proteins expressed in Escherichia coli . Protein Expr. Purif. 48, 151–159 (2006)

    Article  CAS  Google Scholar 

  11. Donskey, C. J. et al. Effect of antibiotic therapy on the density of vancomycin-resistant enterococci in the stool of colonized patients. N. Engl. J. Med. 343, 1925–1932 (2000)

    Article  CAS  Google Scholar 

  12. Miyazaki, S. et al. Development of systemic bacteraemia after oral inoculation of vancomycin-resistant enterococci in mice. J. Med. Microbiol. 50, 695–701 (2001)

    Article  CAS  Google Scholar 

  13. Stiefel, U., Pultz, N. J., Helfand, M. S. & Donskey, C. J. Increased susceptibility to vancomycin-resistant Enterococcus intestinal colonization persists after completion of anti-anaerobic antibiotic treatment in mice. Infect. Control Hosp. Epidemiol. 25, 373–379 (2004)

    Article  Google Scholar 

  14. Wells, C. L., Jechorek, R. P. & Erlandsen, S. L. Evidence for the translocation of Enterococcus faecalis across the mouse intestinal tract. J. Infect. Dis. 162, 82–90 (1990)

    Article  CAS  Google Scholar 

  15. Wells, C. L., Jechorek, R. P., Maddaus, M. A. & Simmons, R. L. Effects of clindamycin and metronidazole on the intestinal colonization and translocation of enterococci in mice. Antimicrob. Agents Chemother. 32, 1769–1775 (1988)

    Article  CAS  Google Scholar 

  16. Sonnenburg, J. L., Chen, C. T. & Gordon, J. I. Genomic and metabolic studies of the impact of probiotics on a model gut symbiont and host. PLoS Biol. 4, e413 (2006)

    Article  Google Scholar 

  17. Pultz, N. J., Stiefel, U., Subramanyan, S., Helfand, M. S. & Donskey, C. J. Mechanisms by which anaerobic microbiota inhibit the establishment in mice of intestinal colonization by vancomycin-resistant Enterococcus . J. Infect. Dis. 191, 949–956 (2005)

    Article  Google Scholar 

  18. Kelly, C. P., Pothoulakis, C. & LaMont, J. T. Clostridium difficile colitis. N. Engl. J. Med. 330, 257–262 (1994)

    Article  CAS  Google Scholar 

  19. Kanzler, H., Barrat, F. J., Hessel, E. M. & Coffman, R. L. Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nature Med. 13, 552–559 (2007)

    Article  CAS  Google Scholar 

  20. Abreu, M. T., Fukata, M. & Arditi, M. TLR signaling in the gut in health and disease. J. Immunol. 174, 4453–4460 (2005)

    Article  CAS  Google Scholar 

  21. Lotz, M., Menard, S. & Hornef, M. Innate immune recognition on the intestinal mucosa. Int. J. Med. Microbiol. 297, 379–392 (2007)

    Article  CAS  Google Scholar 

  22. Cario, E. et al. Lipopolysaccharide activates distinct signaling pathways in intestinal epithelial cell lines expressing Toll-like receptors. J. Immunol. 164, 966–972 (2000)

    Article  CAS  Google Scholar 

  23. Hornef, M. W., Frisan, T., Vandewalle, A., Normark, S. & Richter-Dahlfors, A. Toll-like receptor 4 resides in the Golgi apparatus and colocalizes with internalized lipopolysaccharide in intestinal epithelial cells. J. Exp. Med. 195, 559–570 (2002)

    Article  CAS  Google Scholar 

  24. Ortega-Cava, C. F. et al. Strategic compartmentalization of Toll-like receptor 4 in the mouse gut. J. Immunol. 170, 3977–3985 (2003)

    Article  CAS  Google Scholar 

  25. Pull, S. L., Doherty, J. M., Mills, J. C., Gordon, J. I. & Stappenbeck, T. S. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc. Natl Acad. Sci. USA 102, 99–104 (2005)

    Article  ADS  CAS  Google Scholar 

  26. Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004)

    Article  CAS  Google Scholar 

  27. Nenci, A. et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557–561 (2007)

    Article  ADS  CAS  Google Scholar 

  28. Hammett-Stabler, C. A. & Johns, T. Laboratory guidelines for monitoring of antimicrobial drugs. Clin. Chem. 44, 1129–1140 (1998)

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank L.V. Hooper for providing polyclonal RegIIIγ antiserum, I. Leiner for technical assistance, and W. Falk, B. Salzberger and all members of the Pamer laboratory for discussions. This research was supported by the Alexander von Humboldt Foundation through a Feodor Lynen postdoctoral fellowship to KB and NIH grant AI39031 and AI42135 to EGP.

Author Contributions K.B., G.P., R.P.D. and E.G.P. designed the research. K.B., G.P., C.N.M., C.U., T.J., B.S. and M.F. performed the research. K.B. and E.G.P. analysed the data and wrote the paper.

Author information

Author notes

  1. Katharina Brandl, Coralia N. Mihu & Bernd Schnabl

    Present address: Present addresses: Department of Genetics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA (K.B.); Department of Infectious Diseases, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA (C.N.M.); Department of Medicine, University of California San Diego, La Jolla, California 92093, USA (B.S.).,

Authors and Affiliations

  1. Department of Medicine, Infectious Diseases Service, Immunology Program, Sloan-Kettering Institute,

    Katharina Brandl, Coralia N. Mihu, Carles Ubeda, Ting Jia & Eric G. Pamer

  2. Hepatobiliary Service,,

    George Plitas & Ronald P. DeMatteo

  3. Department of Clinical Laboratories, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA,

    Martin Fleisher & Eric G. Pamer

  4. Department of Medicine, Columbia University, New York, New York 10032, USA,

    Bernd Schnabl

Authors
  1. Katharina Brandl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. George Plitas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Coralia N. Mihu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carles Ubeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ting Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Martin Fleisher
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bernd Schnabl
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ronald P. DeMatteo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Eric G. Pamer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eric G. Pamer.

Supplementary information

Supplementary Information

The file contains Supplementary Figures S1-S8 with Legends. (PDF 271 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brandl, K., Plitas, G., Mihu, C. et al. Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature 455, 804–807 (2008). https://doi.org/10.1038/nature07250

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07250

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing