Bacterial Flagellin Stimulates Toll-Like Receptor 5-Dependent Defense against Vancomycin-Resistant Enterococcus Infection

Infectious Diseases Service, Department of Medicine, Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 02/2010; 201(4):534-43. DOI: 10.1086/650203
Source: PubMed


Treatment of vancomycin-resistant Enterococcus (VRE) infections is limited by the paucity of effective antibiotics. Administration of broad-spectrum antibiotics promotes VRE colonization by down-regulating homeostatic innate immune defenses. Intestinal epithelial cells and Paneth cells express antimicrobial factors on direct or indirect stimulation of the Toll-like receptor (TLR)-myeloid differentiation factor 88-mediated pathway by microbe-derived molecules. Here, we demonstrate that the TLR5 agonist flagellin restores antibiotic-impaired innate immune defenses and restricts colonization with VRE. Flagellin stimulates the expression of RegIIIgamma, a secreted C-type lectin that kills gram-positive bacteria, including VRE. Systemic administration of flagellin induces RegIIIgamma expression in intestinal epithelial cells and Paneth cells along the entire length of the small intestine. Induction of RegIIIgamma requires TLR5 expression in hematopoietic cells and is dependent on interleukin 22 expression. Systemic administration of flagellin to antibiotic-treated mice dramatically reduces VRE colonization. By enhancing mucosal resistance to multidrug-resistant organisms, flagellin administration may provide a clinically useful approach to prevent infections in patients treated with broad-spectrum antibiotics.

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    • "Flagellin preparations from R. hominis A2-183 display potent immuno-modulatory effects (Kelly et al., 2014). In general, signaling by flagellins via TLR5 protects against chemicals, bacteria, viruses, and radiation (Vijay-Kumar et al., 2008) as well as enhances mucosal resistance to colonization by multi-drug resistant pathogens (Kinnebrew et al., 2010). In mice, inhibition of flagellin signaling due to deletion of TLR5 results in spontaneous colitis (Vijay-Kumar et al., 2007). "
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    • "MyD88- dependent bacterial signals induce the repair of a damaged intestinal epithelium (Pull et al. 2005) and promote the induction of epithelial antimicrobial proteins such as RegIIIc. The expression of RegIIIc may be triggered by lipopolysaccharide or flagellin (Brandl et al. 2007; Hooper et al. 2012; Kinnebrew et al. 2010). The commensals that are present in the human body may induce the differentiation of CD4 ? "
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    • "has been shown to enhance pathogen defense by inducing the bactericidal lectin RegIIIg (Zheng et al., 2008), which can inhibit various Gram-positive microbes in vitro (Cash et al., 2006), and limit colonization of vancomycin-resistant Enterococcus faecium (VRE) in the small intestine (Kinnebrew et al., 2010). During C. rodentium infection, Il22ra1 À/À mice indeed showed diminished expression levels of "
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