Brandl, K. et al. Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits. Nature 455, 804-807

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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    ABSTRACT: We previously revealed a negative regulation of LamB in chlortetracycline-resistant Escherichia coli strain. In the present study, we first showed that the negative regulation, which was characterized by decreased abundance of LamB with elevated growth of its gene-deleted mutant in medium with antibiotics, was a general response in resistance to different classes of antibiotics using 2-DE based proteomics or/and genetically gene-deletion mutant of LamB. Then, we revealed the interaction of LamB and Odp1 which catalyzes the overall conversion of pyruvate to acetyl-CoA and CO2, and found the decrease of the complex in antibiotic-resistant strains with a minimum inhibitory concentration dose-dependent manner. Further spectrofluorometry assay indicated that LamB served as a porin to influx an antibiotic. Finally, we showed that the decreased expression of LamB and Odp1 was detected in almost of 34 multidrug-resistant strains, which suggested that LamB and Odp1 were biomarkers for identification of antibiotic-resistance E. coli. Our results indicated that the interaction of an outer membrane protein with an energy metabolic enzyme constructed an efficient pathway to resist antibiotics. These findings provide novel insights into the mechanisms of antibiotics resistance. Our data indicate that the negative regulation by LamB is widely detected in antibiotic-resistant E. coli. LamB serves as a porin to influx an antibiotic and is interacted with Odp1. The complex decreases in antibiotic-resistant strains with a MIC dose-dependent manner. Our findings indicate that interaction of outer membrane protein with energy metabolic enzyme constructs an efficient pathway to resist antibiotics and provides novel insights into the mechanisms of antibiotics resistance.
    Journal of proteomics 01/2014; 98. DOI:10.1016/j.jprot.2013.12.024
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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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    ABSTRACT: Segmented Filamentous Bacteria (SFB) are present in the gut microbiota of a large number of vertebrate species where they are found intimately attached to the intestinal epithelium. SFB has recently attracted considerable attention due to its outstanding capacity to stimulate innate and adaptive host immune responses without causing pathology. Recent genomic analysis placed SFB between obligate and facultative symbionts, unraveled its highly auxotrophic needs, and provided a rationale for the complex SFB life-style in close contact with the epithelium. Herein, we examine how the SFB life-style may underlie its potent immunostimulatory properties and discuss how the trade-off set up between SFB and its hosts can simultaneously help to establish and maintain the ecological niche of SFB in the intestine and drive the post-natal maturation of the host gut immune barrier.
    Seminars in Immunology 10/2013; 25(5). DOI:10.1016/j.smim.2013.09.001
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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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    ABSTRACT: Shifts in commensal microbiota composition are emerging as a hallmark of gastrointestinal inflammation. In particular, outgrowth of γ-proteobacteria has been linked to the etiology of inflammatory bowel disease and the pathologic consequences of infections. Here we show that following acute Toxoplasma gondii gastrointestinal infection of mice, control of commensal outgrowth is a highly coordinated process involving both the host response and microbial signals. Notably, neutrophil emigration to the intestinal lumen results in the generation of organized intraluminal structures that encapsulate commensals and limit their contact with the epithelium. Formation of these luminal casts depends on the high-affinity N-formyl peptide receptor, Fpr1. Consequently, after infection, mice deficient in Fpr1 display increased microbial translocation, poor commensal containment, and increased mortality. Altogether, our study describes a mechanism by which the host rapidly contains commensal pathobiont outgrowth during infection. Further, these results reveal Fpr1 as a major mediator of host commensal interaction during dysbiosis.
    Cell host & microbe 09/2013; 14(3):318-28. DOI:10.1016/j.chom.2013.08.003
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