Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits.
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.
Brandl
Katharina
K
Infectious Diseases Service, Department of Medicine, Immunology Program, Sloan-Kettering Institute, New York, New York, USA.
Plitas
George
G
Mihu
Coralia N
CN
Ubeda
Carles
C
Jia
Ting
T
Fleisher
Martin
M
Schnabl
Bernd
B
DeMatteo
Ronald P
RP
Pamer
Eric G
EG
D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D016983:Enterococcus / Q000187:drug effects* / Q000276:immunology / Q000502:physiology*; D007113:Immunity, Innate / Q000187:drug effects* / Q000276:immunology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D014640:Vancomycin / Q000378:metabolism / Q000494:pharmacology*; D020713:Vancomycin Resistance
D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; C490255:Reg3g protein, mouse; D051197:Toll-Like Receptor 4; D014640:Vancomycin