title: Gut microbial translocation corrupts myeloid cell function to control bacterial infection during liver cirrhosis.
abstract: Patients with liver cirrhosis suffer from increased susceptibility to life-threatening bacterial infections that cause substantial morbidity.
  
  
  
  Experimental liver fibrosis in mice induced by bile duct ligation or CCl4application was used to characterise the mechanisms determining failure of innate immunity to control bacterial infections.
  
  
  
  In murine liver fibrosis, translocation of gut microbiota induced tonic type I interferon (IFN) expression in the liver. Such tonic IFN expression conditioned liver myeloid cells to produce high concentrations of IFN upon intracellular infection withListeriathat activate cytosolic pattern recognition receptors. Such IFN-receptor signalling caused myeloid cell interleukin (IL)-10 production that corrupted antibacterial immunity, leading to loss of infection-control and to infection-associated mortality. In patients with liver cirrhosis, we also found a prominent liver IFN signature and myeloid cells showed increased IL-10 production after bacterial infection. Thus, myeloid cells are both source and target of IFN-induced and IL-10-mediated immune dysfunction. Antibody-mediated blockade of IFN-receptor or IL-10-receptor signalling reconstituted antibacterial immunity and prevented infection-associated mortality in mice with liver fibrosis.
  
  
  
  In severe liver fibrosis and cirrhosis, failure to control bacterial infection is caused by augmented IFN and IL-10 expression that incapacitates antibacterial immunity of myeloid cells. Targeted interference with the immune regulatory host factors IL-10 and IFN reconstitutes antibacterial immunity and may be used as therapeutic strategy to control bacterial infections in patients with liver cirrhosis.
authors.affiliation: Institute of Experimental Immunology, Universität Bonn, Bonn, Germany.
authors.forename: Carl-Philipp
authors.initials: CP
authors.lastname: Hackstein
authors.affiliation: Institute of Experimental Immunology, Universität Bonn, Bonn, Germany.
authors.forename: Lisa Mareike
authors.initials: LM
authors.lastname: Assmus
authors.affiliation: Institute of Experimental Immunology, Universität Bonn, Bonn, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Welz
authors.affiliation: Department of Internal Medicine I, Universität Bonn, Bonn, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Klein
authors.affiliation: Institute of Experimental Immunology, Universität Bonn, Bonn, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Schwandt
authors.affiliation: Genomics and Immunoregulation, LIMES Institute, Universität Bonn, Bonn, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Schultze
authors.affiliation: Immunology and Environment, LIMES Institute, Universität Bonn, Bonn, Germany.
authors.forename: Irmgard
authors.initials: I
authors.lastname: Förster
authors.affiliation: Immunology and Environment, LIMES Institute, Universität Bonn, Bonn, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Gondorf
authors.affiliation: Genomics and Immunoregulation, LIMES Institute, Universität Bonn, Bonn, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Beyer
authors.affiliation: Department of Medicine III, University Hospital Aachen, Aachen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Kroy
authors.affiliation: Institute of Experimental Immunology, Universität Bonn, Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
authors.affiliation: Department of Internal Medicine I, Universität Bonn, Bonn, Germany.
authors.forename: Jonel
authors.initials: J
authors.lastname: Trebicka
authors.affiliation: Institute of Experimental Immunology, Universität Bonn, Bonn, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kastenmüller
authors.affiliation: Institute of Experimental Immunology, Universität Bonn, Bonn, Germany.|Institute of Molecular Immunology and Experimental Oncology, Technische Universität München, München, Germany.
authors.forename: Percy A
authors.initials: PA
authors.lastname: Knolle
authors.affiliation: Institute of Experimental Immunology, Universität Bonn, Bonn, Germany.
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Abdullah
mesh_terms: D000818:Animals; D018988:Bacterial Translocation; D002251:Carbon Tetrachloride; D007113:Immunity, Innate / Q000235:genetics; D007370:Interferon Type I / Q000378:metabolism*; D016753:Interleukin-10 / Q000096:biosynthesis*; D008088:Listeriosis / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D064547:Myxovirus Resistance Proteins / Q000235:genetics; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors / Q000235:genetics; D053701:Receptors, Interleukin-10 / Q000037:antagonists & inhibitors; D051192:Receptors, Pattern Recognition / Q000235:genetics; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics; D051199:Toll-Like Receptor 7 / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000235:genetics
chemical_list: D007370:Interferon Type I; D008562:Membrane Glycoproteins; C579070:Mx1 protein, mouse; D064547:Myxovirus Resistance Proteins; D053701:Receptors, Interleukin-10; D051192:Receptors, Pattern Recognition; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D016753:Interleukin-10; D053633:Receptor, Interferon alpha-beta; D002251:Carbon Tetrachloride
keywords: BACTERIAL INFECTION; HEPATIC FIBROSIS; IMMUNE RESPONSE; LIVER CIRRHOSIS; LIVER IMMUNOLOGY