title: Hepcidin-mediated iron sequestration protects against bacterial dissemination during pneumonia.
abstract: Gram-negative pneumonia is a dangerous illness, and bacterial dissemination to the bloodstream during the infection is strongly associated with death. Antibiotic resistance among the causative pathogens has resulted in diminishing treatment options against this infection. Hepcidin is the master regulator of extracellular iron availability in vertebrates, but its role in the context of host defense is undefined. We hypothesized that hepcidin-mediated depletion of extracellular iron during Gram-negative pneumonia protects the host by limiting dissemination of bacteria to the bloodstream. During experimental pneumonia, hepcidin was induced in the liver in an IL-6-dependent manner and mediated a rapid decline in plasma iron. In contrast, hepcidin-deficient mice developed a paradoxical increase in plasma iron during infection associated with profound susceptibility to bacteremia. Incubation of bacteria with iron-supplemented plasma enhanced bacterial growth in vitro, and systemic administration of iron to WT mice similarly promoted increased susceptibility to bloodstream infection. Finally, treatment with a hepcidin analogue restored hypoferremia in hepcidin-deficient hosts, mediated bacterial control, and improved outcomes. These data show hepcidin induction during pneumonia to be essential to preventing bacterial dissemination by limiting extracellular iron availability. Hepcidin agonists may represent an effective therapy for Gram-negative infections in patients with impaired hepcidin production or signaling.
authors.affiliation: Departments of Microbiology, Immunology, and Cancer Biology.
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Michels
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Departments of Microbiology, Immunology, and Cancer Biology.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Bettina
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: R Elaine
authors.initials: RE
authors.lastname: Cagnina
authors.affiliation: Departments of Molecular, Cellular, and Integrative Physiology, University of California, Los Angeles, California, USA.
authors.forename: Debora
authors.initials: D
authors.lastname: Stefanova
authors.affiliation: Division of Pulmonary & Critical Care Medicine, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Marie D
authors.initials: MD
authors.lastname: Burdick
authors.affiliation: INSERM U1016, Cochin Institute, Descartes University, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Vaulont
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Elizabeta
authors.initials: E
authors.lastname: Nemeth
authors.affiliation: Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
authors.forename: Tomas
authors.initials: T
authors.lastname: Ganz
authors.affiliation: Departments of Microbiology, Immunology, and Cancer Biology.|Division of Pulmonary & Critical Care Medicine, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.|Beirne B. Carter Center for Immunology, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Borna
authors.initials: B
authors.lastname: Mehrad
mesh_terms: D000818:Animals; D001682:Biological Availability; D001992:Bronchoalveolar Lavage Fluid; D064451:Hepcidins / Q000502:physiology*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007711:Klebsiella pneumoniae / Q000254:growth & development* / Q000302:isolation & purification; D051379:Mice; D018410:Pneumonia, Bacterial / Q000382:microbiology*
chemical_list: D064451:Hepcidins; D007501:Iron