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Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits

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.

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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.

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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.

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Correspondence to Eric G. Pamer.

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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

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