Hepcidin-Induced Hypoferremia Is a Critical Host Defense Mechanism against the Siderophilic Bacterium Vibrio vulnificus

• Published in: Cell host & microbe Vol. 17; no. 1; pp. 47 - 57
• Main Authors: Arezes, João, Jung, Grace, Gabayan, Victoria, Valore, Erika, Ruchala, Piotr, Gulig, Paul A., Ganz, Tomas, Nemeth, Elizabeta, Bulut, Yonca
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.01.2015
• Subjects: Animals; Bacteremia - immunology; Bacteremia - microbiology; Bacterial Load; Defense Mechanisms; Hepcidins - deficiency; Hepcidins - metabolism; Iron - blood; Iron - metabolism; Mice, Inbred C57BL; Mice, Knockout; Vibrio Infections - immunology; Vibrio Infections - microbiology; Vibrio vulnificus - growth & development; Vibrio vulnificus - immunology
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2014.12.001

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. [Display omitted] •During V. vulnificus infection, hepcidin is induced within hours, causing hypoferremia•Iron overload and hepcidin deficiency predispose mice to V. vulnificus infection•Hepcidin-induced hypoferremia restricts bacterial growth, even during iron overload•Treatment with hepcidin agonists averted mortality from V. vulnificus infection The hepatic hormone hepcidin is a key regulator of iron homeostasis. Arezes et al. demonstrate that hepcidin is critical for host defense against Vibrio vulnificus, a deadly bacterial pathogen. Treatment with hepcidin agonist averted mortality in infected mice, highlighting the potential of hepcidin therapy in siderophilic infections.