title: A human macrophage-hepatocyte co-culture model for comparative studies of infection and replication of Francisella tularensis LVS strain and subspecies holarctica and mediasiatica.
abstract: BACKGROUND
  Francisella tularensis, a gram-negative bacterium replicates intracellularly within macrophages and efficiently evades the innate immune response. It is able to infect and replicate within Kupffer cells, specialized tissue macrophages of the liver, and to modulate the immune response upon infection to its own advantage. Studies on Francisella tularensis liver infection were mostly performed in animal models and difficult to extrapolate to the human situation, since human infections and clinical observations are rare.
  
  
  RESULTS
  Using a human co-culture model of macrophages and hepatocytes we investigated the course of infection of three Francisella tularensis strains (subspecies holarctica--wildtype and live vaccine strain, and mediasiatica--wildtype) and analyzed the immune response triggered upon infection. We observed that hepatocytes support the intracellular replication of Franciscella species in macrophages accompanied by a specific immune response inducing TNFα, IL-1β, IL-6 and fractalkine (CX3CL1) secretion and the induction of apoptosis.
  
  
  CONCLUSIONS
  We could demonstrate that this human macrophage/hepatocyte co-culture model reflects strain-specific virulence of Francisella tularensis. We developed a suitable tool for more detailed in vitro studies on the immune response upon liver cell infection by F. tularensis.
authors.affiliation: Institute of Biochemistry II, Jena University Hospital, 07743, Jena, Germany. knut.rennert@med.uni-jena.de.
authors.forename: Knut
authors.initials: K
authors.lastname: Rennert
authors.affiliation: Institute of Bacterial Infections and Zoonoses (IBIZ), Friedrich-Loeffler-Institute, Federal Research Institute for Animal Health, 07743, Jena, Germany. gps.otto@t-online.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Otto
authors.affiliation: Molecular Hemostaseology, Jena University Hospital, 07743, Jena, Germany. harald.funke@med.uni-jena.de.
authors.forename: Harald
authors.initials: H
authors.lastname: Funke
authors.affiliation: Institute of Biochemistry II, Jena University Hospital, 07743, Jena, Germany. otmar.huber@med.uni-jena.de.|Center for Sepsis Control and Care, Jena University Hospital, Jena, 07747, Germany. otmar.huber@med.uni-jena.de.
authors.forename: Otmar
authors.initials: O
authors.lastname: Huber
authors.affiliation: Institute of Bacterial Infections and Zoonoses (IBIZ), Friedrich-Loeffler-Institute, Federal Research Institute for Animal Health, 07743, Jena, Germany. herbert.tomaso@fli.bund.de.
authors.forename: Herbert
authors.initials: H
authors.lastname: Tomaso
authors.affiliation: Institute of Biochemistry II, Jena University Hospital, 07743, Jena, Germany. alexander.mosig@med.uni-jena.de.|Center for Sepsis Control and Care, Jena University Hospital, Jena, 07747, Germany. alexander.mosig@med.uni-jena.de.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Mosig
mesh_terms: D017209:Apoptosis; D001428:Bacterial Vaccines / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods*; D005604:Francisella tularensis / Q000145:classification / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000166:cytology / Q000276:immunology / Q000382:microbiology*; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000382:microbiology*; D014406:Tularemia / Q000276:immunology / Q000382:microbiology* / Q000503:physiopathology
chemical_list: D001428:Bacterial Vaccines; D053583:Interleukin-1beta; D015850:Interleukin-6