Article

Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits.

Infectious Diseases Service, Department of Medicine, Immunology Program, Sloan-Kettering Institute, New York, New York, USA.
Nature (Impact Factor: 42.35). 09/2008; 455(7214):804-7. DOI: 10.1038/nature07250
Source: PubMed

ABSTRACT Infection with antibiotic-resistant bacteria, such as vancomycin-resistant Enterococcus (VRE), is a dangerous and costly complication of broad-spectrum antibiotic therapy. 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.

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    • "There is an urgent need to uncover bacterial drugresistant mechanisms to combat the antibiotic-resistant pathogens and cure the consequently infectious diseases. A line of evidences has indicated that bacteria developed several strategies to cope with antibiotic treatments, including gene mutation of target protein, transferring of antibiotic resistance plasmids, modifications of enzymatically degrading and target sites, decreasing of permeability, and activation of efflux system [1] [2] [3]. In particular, Gram-negative bacteria, which "
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    • "The loss of SFB may not only facilitate colonization by a Gram-negative pathogen such as S. Typhimurium as shown by Croswell et al. [65], but may also predispose the host to the outgrowth of opportunistic Gram-positive bacteria. This possibility is suggested by the strong induction by SFB of the microbicide peptide Reg3␥ [30] [45] [54], the downregulation of which after antibiotic therapy was shown to promote colonization by Vancomycin-resistant enterococcus [66]. The mechanism(s) of the barrier effect of SFB is (are), however, not delineated and more studies are necessary to define whether SFB interferes directly with pathogens by blocking their attachment or competing for nutrients or indirectly by stimulating host defense. "
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    • "This is accomplished by establishment of a structural and immunological barrier, referred to as the mucosal firewall, resulting from the combined action of mucus, IgA, and antimicrobial proteins (Hooper et al., 2012). Under steady-state conditions, commensals can promote their own containment by enhancing various aspects of this physical and immunological barrier (Brandl et al., 2008; Vaishnava et al., 2011). The gastrointestinal (GI) tract represents one of the primary sites of exposure to pathogens. "
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