Bacterial Flagellin Stimulates Toll‐Like Receptor 5–Dependent Defense against Vancomycin‐ResistantEnterococcusInfection

Abstract

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 upon direct or indirect stimulation of the Toll-like receptor (TLR)-MyD88-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 RegIIIγ, a secreted C-type lectin that kills Gram-positive bacteria, including VRE. Systemic administration of flagellin induces RegIIIγ expression in intestinal epithelial cells and Paneth cells along the entire length of the small intestine. Induction of RegIIIγ requires TLR5 expression in hematopoietic cells and is dependent on IL-22 expression. Systemic administration of flagellin to antibiotic-treated mice dramatically reduces VRE colonization. By enhancing mucosal resistance to multi-drug resistant organisms, flagellin administration may provide a clinically useful approach to prevent infections in patients treated with broad-spectrum antibiotics.

TLR5 Signaling Stimulates the Innate Production of IL-17 and IL-22 by CD3negCD127+ Immune Cells in Spleen and Mucosa

“…The effect of TLR signaling on IL-17 and IL-22 was previously suggested because their synthesis was enhanced after administration of TLR2 and TLR4 agonists (12,29). Very recently, TLR5 signaling was also associated to such response (40). In this study, we analyzed the immune response to the TLR5 activator The Journal of Immunologyflagellin, with a focus on mucosa.…”

“…Flagellin-mediated protection of rodents and nonhuman primates against lethal irradiation was associated with CSF3-mediated granulopoiesis and the antiapoptotic effect of superoxide dismutase 2 (47). Flagellin treatment has been linked to resistance against inflammatory colitis and gut infections (40,48). The TLR5-induced circulating and local production of IL-17/IL-22 may be the main driving force behind these protective effects.…”

“…The TLR5-induced circulating and local production of IL-17/IL-22 may be the main driving force behind these protective effects. The contribution of IL-22 was recently suggested as instrumental in the control of infection with enterococci (40). In response to IL-17R and IL-22R signaling, epithelial and stromal cells produce antimicrobial peptides (RegIII), CXC chemokines, and growth factors (CSF3) for neutrophils, all of which are involved in mucosal protection (3)(4)(5)(6)(7)38).…”

Gut Microbiome-Brain Communications Regulate Host Physiology and Behavior

“…Specifically, differentiation of Th17 cells in the lamina propria of the small intestine is correlated with the presence of bacteria from the Cytophaga-FlavobacteriumBacteroides group [92]. Additionally, the stimulation of TLR5, mediated by flagellin, triggers the expression of IL-6, inducing Th17 cell programming [93]. Moreover, polysaccharide A from B. fragilis can protect from inflammatory diseases such as colitis by suppressing pro-inflammatory IL-17-producing CD4 + T cells and inducing IL-10-producing CD4 + T cells [94].…”

Fecal microbiota transplantation: effectiveness, complexities, and lingering concerns

“…46 Administration of oral lipopolysaccharide or systemic flagellin to antibiotic-treated mice re-induces RegIIIg expression and reduces intestinal colonization with VRE. 46,47 Recent studies using the mouse model demonstrated that stimulation of TLR5 with flagellin increases resistance to C. difficile infection. 48 Although it is unclear whether TLR5-mediated protection against C. difficile infection is mediated by RegIIIg, recent studies have demonstrated that MyD88-deficient mice are highly susceptible to C. difficile infection and that MyD88-signaling is required for neutrophil recruitment to the gut, an essential step for survival of infection.…”