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Cell Host Microbe. 2015 Jan 14;17(1):47-57. doi: 10.1016/j.chom.2014.12.001.

Hepcidin-induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium Vibrio vulnificus.

Author information

1
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.
2
David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
3
Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32601, USA.
4
David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA. Electronic address: tganz@mednet.ucla.edu.

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.

PMID:
25590758
PMCID:
PMC4296238
DOI:
10.1016/j.chom.2014.12.001
[Indexed for MEDLINE]
Free PMC Article

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