title: Host innate recognition of an intestinal bacterial pathogen induces TRIF-dependent protective immunity.
abstract: Toll-like receptor 4 (TLR4), which signals through the adapter molecules myeloid differentiation factor 88 (MyD88) and toll/interleukin 1 receptor domain-containing adapter inducing IFN-β (TRIF), is required for protection against Gram-negative bacteria. TRIF is known to be important in TLR3-mediated antiviral signaling, but the role of TRIF signaling against Gram-negative enteropathogens is currently unknown. We show that TRIF signaling is indispensable for establishing innate protective immunity against Gram-negative Yersinia enterocolitica. Infection of wild-type mice rapidly induced both IFN-β and IFN-γ in the mesenteric lymph nodes. In contrast, TRIF-deficient mice were defective in these IFN responses and showed impaired phagocytosis in regional macrophages, resulting in greater bacterial dissemination and mortality. TRIF signaling may be universally important for protection against Gram-negative pathogens, as TRIF-deficient macrophages were also impaired in killing both Salmonella and Escherichia coli in vitro. The mechanism of TRIF-mediated protective immunity appears to be orchestrated by macrophage-induced IFN-β and NK cell production of IFN-γ. Sequential induction of IFN-β and IFN-γ leads to amplification of macrophage bactericidal activity sufficient to eliminate the invading pathogens at the intestinal interface. Our results demonstrate a previously unknown role of TRIF in host resistance to Gram-negative enteropathogens, which may lead to effective strategies for combating enteric infections.
authors: Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors: John
authors: J
authors: Sotolongo
authors: Cecilia
authors: C
authors: España
authors: Andrea
authors: A
authors: Echeverry
authors: David
authors: D
authors: Siefker
authors: Norman
authors: N
authors: Altman
authors: Julia
authors: J
authors: Zaias
authors: Rebeca
authors: R
authors: Santaolalla
authors: Jose
authors: J
authors: Ruiz
authors: Kurt
authors: K
authors: Schesser
authors: Becky
authors: B
authors: Adkins
authors: Masayuki
authors: M
authors: Fukata
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology*; D000818:Animals; D006090:Gram-Negative Bacteria / Q000276:immunology*; D016905:Gram-Negative Bacterial Infections / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate / Q000502:physiology*; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016899:Interferon-beta; D007371:Interferon-gamma; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse