title: Hepcidin-induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium Vibrio vulnificus.
abstract: Hereditary hemochromatosis, an iron overload disease caused by a deficiency in the iron-regulatory hormone hepcidin, is associated with lethal infections by siderophilic bacteria. To elucidate the mechanisms of this susceptibility, we infected wild-type and hepcidin-deficient mice with the siderophilic bacterium Vibrio vulnificus and found that hepcidin deficiency results in increased bacteremia and decreased survival of infected mice, which can be partially ameliorated by dietary iron depletion. Additionally, timely administration of hepcidin agonists to hepcidin-deficient mice induces hypoferremia that decreases bacterial loads and rescues these mice from death, regardless of initial iron levels. Studies of Vibrio vulnificus growth ex vivo show that high iron sera from hepcidin-deficient mice support extraordinarily rapid bacterial growth and that this is inhibited in hypoferremic sera. Our findings demonstrate that hepcidin-mediated hypoferremia is a host defense mechanism against siderophilic pathogens and suggest that hepcidin agonists may improve infection outcomes in patients with hereditary hemochromatosis or thalassemia.
authors.affiliation: David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto 4050, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Arezes
authors.affiliation: David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Jung
authors.affiliation: David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Gabayan
authors.affiliation: David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Valore
authors.affiliation: David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Ruchala
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32601, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Gulig
authors.affiliation: David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Electronic address: tganz@mednet.ucla.edu.
authors.forename: Tomas
authors.initials: T
authors.lastname: Ganz
authors.affiliation: David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Elizabeta
authors.initials: E
authors.lastname: Nemeth
authors.affiliation: David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: Yonca
authors.initials: Y
authors.lastname: Bulut
mesh_terms: D000818:Animals; D016470:Bacteremia / Q000276:immunology* / Q000382:microbiology; D058491:Bacterial Load; D003674:Defense Mechanisms; D064451:Hepcidins / Q000172:deficiency / Q000378:metabolism*; D007501:Iron / Q000097:blood / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014735:Vibrio Infections / Q000276:immunology* / Q000382:microbiology; D041261:Vibrio vulnificus / Q000254:growth & development* / Q000276:immunology*
chemical_list: D064451:Hepcidins; D007501:Iron