Hepcidin Protects against Lethal Escherichia coli Sepsis in Mice Inoculated with Isolates from Septic Patients
Open accessAbstract
Iron is an essential micronutrient for most microbes and their hosts. Mammalian hosts respond to infection by inducing the iron-regulatory hormone hepcidin, which causes iron sequestration and a rapid decrease in the plasma and extracellular iron concentration (hypoferremia). Previous studies showed that hepcidin regulation of iron is essential for protection from infection-associated mortality with the siderophilic pathogens Yersinia enterocolitica and Vibrio vulnificus . However, the evolutionary conservation of the hypoferremic response to infection suggests that not only rare siderophilic bacteria but also common pathogens may be targeted by this mechanism. We tested 10 clinical isolates of Escherichia coli from children with sepsis and found that both genetic iron overload (by hepcidin-1 knockout [HKO]) and iatrogenic iron overload (by intravenous iron) potentiated infection with 8 out of the 10 studied isolates: after peritoneal injection of E. coli , iron-loaded mice developed sepsis with 60% to 100% mortality within 24 h, while control wild-type mice suffered 0% mortality. Using one strain for more detailed study, we show that iron overload allows rapid bacterial multiplication and dissemination. We further found that the presence of non-transferrin-bound iron (NTBI) in the circulation is more important than total plasma or tissue iron in rendering mice susceptible to infection and mortality. Postinfection treatment of HKO mice with just two doses of the hepcidin agonist PR73 abolished NTBI and completely prevented sepsis-associated mortality. We demonstrate that the siderophilic phenotype extends to clinically common pathogens. The use of hepcidin agonists promises to be an effective early intervention in patients with infections and dysregulated iron metabolism.
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This form of nutritional immunity is particularly important in infections with gram negative bacteria and some fungi.
“This form of “nutritional immunity” is particularly important in infections with gram negative bacteria and some fungi ([54,56,57,58].”
From Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis (2021) · cites this paper as [56]
HAMP plays a role in preventing uncontrolled systemic infection with extracellular bacteria, including Vibrio vulnificus, Yersinia enterocolitica and some pathogenic Escherichia coli variants.
“Serum iron deficiency in humans is protective against the growth of some bacteria, 99 and HAMP plays a role in preventing uncontrolled systemic infection with extracellular bacteria – including Vibrio vulnificus, Yersinia enterocolitica and some pathogenic Escherichia coli variants. 100 , 101 , 102 , 103”
From The battle for iron in enteric infections (2020) · cites this paper as [101]
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- Authors
- Stefanova, D., Raychev, A., Deville, J., Humphries, R., Campeau, S., Ruchala, P., Nemeth, E., Ganz, T., & Bulut, Y.
- Affiliations
- University of California, Los Angeles (US)
- ORCID
- Venue
- Infection and Immunity
- Publisher
- American Society for Microbiology
- Published
- 2018-07
- Volume
- 86
- Issue
- 7
- ISSN
- 0019-9567 (ISSN-L)
- 1098-5522
- PMC
- PMC6013672
- OpenAlex
- W2801429697
- Semantic Scholar
- df26bba43508542751a64650d500f8990142e7e6
- Cited by
- 68
- References
- 45
- Citations by year
- 2026: 11 · 2025: 8 · 2024: 4 · 2023: 8 · 2022: 6 · 2021: 7 · 2020: 9 · 2019: 10 · 2018: 5
- FWCI
- 5.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Infection and Immunity (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- HHS | National Institutes of Health (R01DK107309, R01DK065029)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Escherichia coli research studies
- Keywords
- hepcidin, Escherichia coli sepsis, hypoferremia, iron overload, non-transferrin-bound iron, bacterial dissemination, pediatric sepsis
- MeSH terms
- Animals, Child, Escherichia coli Infections, Humans, Iron, Mice, Inbred C57BL, Transferrin, Bacteremia, Mice, Knockout, Iron Overload, Mice, Hepcidins
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