Abstract
The iron-regulatory hormone hepcidin is induced early in infection, causing iron sequestration in macrophages and decreased plasma iron; this is proposed to limit the replication of extracellular microbes, but could also promote infection with macrophage-tropic pathogens. The mechanisms by which hepcidin and hypoferremia modulate host defense, and the spectrum of microbes affected, are poorly understood. Using mouse models, we show that hepcidin was selectively protective against siderophilic extracellular pathogens (Yersinia enterocolitica O9) by controlling non-transferrin-bound iron (NTBI) rather than iron-transferrin concentration. NTBI promoted the rapid growth of siderophilic but not nonsiderophilic bacteria in mice with either genetic or iatrogenic iron overload and in human plasma. Hepcidin or iron loading did not affect other key components of innate immunity, did not indiscriminately promote intracellular infections (Mycobacterium tuberculosis), and had no effect on extracellular nonsiderophilic Y enterocolitica O8 or Staphylococcus aureus Hepcidin analogs may be useful for treatment of siderophilic infections.
© 2017 by The American Society of Hematology.
MeSH terms
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Animals
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Binding, Competitive
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Catheter-Related Infections / immunology*
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Catheter-Related Infections / metabolism
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Catheter-Related Infections / microbiology
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Catheter-Related Infections / mortality
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Disease Models, Animal
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Disease Resistance
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Gene Expression
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Hemochromatosis / immunology*
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Hemochromatosis / metabolism
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Hemochromatosis / microbiology
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Hemochromatosis / mortality
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Hepcidins / agonists
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Hepcidins / deficiency
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Hepcidins / genetics
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Hepcidins / immunology*
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Humans
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Iron / immunology
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Iron / metabolism*
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Iron Overload / immunology*
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Iron Overload / metabolism
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Iron Overload / microbiology
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Iron Overload / mortality
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mycobacterium tuberculosis / drug effects
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Mycobacterium tuberculosis / growth & development
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Mycobacterium tuberculosis / metabolism
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Oligopeptides / pharmacology
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Protein Binding
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Staphylococcal Infections / immunology*
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Staphylococcal Infections / metabolism
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Staphylococcal Infections / microbiology
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Staphylococcal Infections / mortality
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Staphylococcus aureus
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Survival Analysis
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Transferrin / genetics
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Transferrin / metabolism
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Yersinia enterocolitica / drug effects
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Yersinia enterocolitica / growth & development
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Yersinia enterocolitica / metabolism
Substances
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Hamp protein, mouse
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Hepcidins
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Oligopeptides
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Transferrin
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Iron