Bacterial flagellin stimulates Toll-like receptor 5-dependent defense against vancomycin-resistant Enterococcus infection.
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.
Kinnebrew
Melissa A
MA
Infectious Diseases Service, Department of Medicine, Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Ubeda
Carles
C
Zenewicz
Lauren A
LA
Smith
Nichole
N
Flavell
Richard A
RA
Pamer
Eric G
EG
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002452:Cell Count; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D016983:Enterococcus / Q000187:drug effects*; D005260:Female; D005408:Flagellin / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects; D007150:Immunohistochemistry; D007378:Interleukins / Q000276:immunology / Q000378:metabolism; D007421:Intestine, Small / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051198:Toll-Like Receptor 5 / Q000819:agonists* / Q000276:immunology / Q000378:metabolism; D020713:Vancomycin Resistance / Q000187:drug effects* / Q000276:immunology; D000097043:Interleukin-22
D000900:Anti-Bacterial Agents; D016207:Cytokines; D005408:Flagellin; D007378:Interleukins; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; D051198:Toll-Like Receptor 5; D000097043:Interleukin-22; C490253:Reg3b protein, mouse; C490255:Reg3g protein, mouse