Nature 455, 804-807 (9 October 2008) | doi:10.1038/nature07250; Received 28 May 2008; Accepted 14 July 2008; Published online 24 August 2008

Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits

Katharina Brandl1,5, George Plitas2, Coralia N. Mihu1,5, Carles Ubeda1, Ting Jia1, Martin Fleisher3, Bernd Schnabl4,5, Ronald P. DeMatteo2 & Eric G. Pamer1,3

  1. Infectious Diseases Service, Department of Medicine, Immunology Program, Sloan-Kettering Institute
  2. Hepatobiliary Service,
  3. Department of Clinical Laboratories, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA
  4. Department of Medicine, Columbia University, New York, New York 10032, USA
  5. 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.).

Correspondence to: Eric G. Pamer1,3 Correspondence and requests for materials should be addressed to E.G.P. (Email: pamere@mskcc.org).

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 RegIIIgamma (also known as Reg3g), a secreted C-type lectin that kills Gram-positive bacteria, including VRE. Downregulation of RegIIIgamma 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 RegIIIgamma, 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.