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

被引:192
作者
Arezes, Joao [1 ,2 ]
Jung, Grace [1 ]
Gabayan, Victoria [1 ]
Valore, Erika [1 ]
Ruchala, Piotr [1 ]
Gulig, Paul A. [3 ]
Ganz, Tomas [1 ]
Nemeth, Elizabeta [1 ]
Bulut, Yonca [1 ]
机构
[1] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA
[2] Univ Porto, Abel Salazar Biomed Sci Inst, Grad Program Areas Basic & Appl Biol, P-4050 Oporto, Portugal
[3] Univ Florida, Dept Mol Genet & Microbiol, Gainesville, FL 32601 USA
关键词
HUMAN MONOCYTIC CELLS; IRON OVERLOAD; SEVERE HEMOCHROMATOSIS; ENVIRONMENTAL STRAINS; MEDIATED REGULATION; MOUSE MODEL; INFECTION; MICE; PATHOGENESIS; PEPTIDE;
D O I
10.1016/j.chom.2014.12.001
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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.
引用
收藏
页码:47 / 57
页数:11
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