Absence of functional Hfe protects mice from invasive Salmonella enterica Serovar Typhimurium infection via induction of lipocalin-2
Open accessAbstract
Mutations of HFE are associated with hereditary hemochromatosis, but their influence on host susceptibility to infection is incompletely understood. We report that mice lacking one or both Hfe alleles are protected from septicemia with Salmonella Typhimurium, displaying prolonged survival and improved control of bacterial replication. This increased resistance is paralleled by an enhanced production of the enterochelin-binding peptide lipocalin-2 (Lcn2), which reduces the availability of iron for Salmonella within Hfe-deficient macrophages. Accordingly, Hfe−/−Lcn2−/− macrophages are unable to efficiently control the infection or to withhold iron from intracellular Salmonella. Correspondingly, the protection conferred by the Hfe defect is abolished in Hfe−/− mice infected with enterochelin-deficient Salmonella as well as in Hfe−/−Lcn2−/− mice infected with wild-type bacteria. Thus, by induction of the iron-capturing peptide Lcn2, absence of functional Hfe confers host resistance to systemic infection with Salmonella, thereby providing an evolutionary advantage which may account for the high prevalence of genetic hemochromatosis.
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Infections with intracellular microorganisms that reside in macrophages may be enhanced by hepcidin-induced iron sequestration, and hepcidin deficiency in mouse models of hereditary haemochromatosis may inhibit growth of macrophage-resident bacteria including M. tuberculosis and S. Typhimurium.
“Paradoxically, studies in mouse models have shown that infections with intracellular microorganisms that reside in macrophages may be enhanced by hepcidin-induced iron sequestration, and conversely, hepcidin deficiency in mouse models of hereditary haemochromatosis may inhibit the growth of macrophage-resident bacteria, including Mycobacteria tuberculosis53 or Salmonella enterica serovar enterica”
From Iron homeostasis in host defence and inflammation (2015) · cites this paper as [54]
The beneficial effect in Hfe−/− mice was linked to increased formation of Lcn2, and improved control of infection was abolished in Hfe−/− and Lcn2−/− double knockout mice.
“This beneficial effect was linked to increased formation of lipocalin-2 (Lcn2) by Hfe−/− mice, whereas the improved control of infection was abolished in Hfe−/− and Lcn2−/− double knockout mice (204).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [204]
Hfe−/− mice controlled invasive S. typhimurium infection significantly better than wildtype littermates, with reduced bacterial burden in spleen and liver and improved survival.
“These mice were able to control invasive infection with S. typhimurium significantly better than wildtype littermates, which translated into reduced bacterial burden in spleen and liver and improved survival of Hfe−/− mice (204).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [204]
Induction of Lcn2 expression is involved in the mechanism protecting mice lacking HFE from Salmonella infection.
“Nonetheless, induction of Lcn2 expression is also involved in the mechanism that protects mice lacking the hemochromatosis protein (HFE) from Salmonella infection [159].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [159]
Hfe knockout mice and macrophages of hemochromatosis patients presented with improved control of infections with intracellular bacteria, Salmonella Typhimurium or Mycobacterium tuberculosis, respectively, which could be referred to immune-modulatory properties of HFE but largely to stimulation of cellular iron egress via LCN2 formation.
“Hfe knock out mice and macrophages of hemochromatosis patients presented with an improved control of infections with intracellular bacteria, Salmonella Typhimurium or Mycobacterium tuberculosis, respectively, which could be referred to immune-modulatory properties of HFE but largely to stimulation of cellular iron egress via LCN2 formation”
From Iron in immune cell function and host defense (2021) · cites this paper as [43]
In intracellular S. Typhimurium infection, Hfe-deficient macrophages are iron-poor and provide an inferior niche for bacterial replication.
“However, the opposite is true in the context of infection with an intracellular bacterium such as S. Typhimurium because Hfe-deficient macrophages are iron-poor and thus provide an inferior niche for bacterial replication (Nairz et al., 2009).”
From Genetic and Dietary Iron Overload Differentially Affect the Course of Salmonella Typhimurium Infection (2017) · cites this paper as Nairz et al., 2009
In vitro data generally support the role of hepcidin in promoting Salmonella growth in macrophages.
“Although in vitro data generally support the role of hepcidin in promoting Salmonella growth in macrophages, in vivo studies have provided conflicting results.”
From Hepcidin and Host Defense against Infectious Diseases (2015) · cites this paper as [40]
The literature on the susceptibility of Hfe-deficient mice to salmonellosis is contradictory.
“The literature on the susceptibility of Hfe-deficient mice to salmonellosis is also contradictory.”
From Hepcidin and Host Defense against Infectious Diseases (2015) · cites this paper as [40]
The detrimental effect of hepcidin in intracellular infections is not supported by in vivo data.
“but is not supported by in vivo data [32,39–43,49–55]”
From Hepcidin and Host Defense against Infectious Diseases (2015) · cites this paper as [40]
The detrimental effect of hepcidin in intracellular infections has been demonstrated convincingly in vitro.
“This effect has been demonstrated convincingly in vitro”
From Hepcidin and Host Defense against Infectious Diseases (2015) · cites this paper as [40]
Hepcidin induces iron accumulation in macrophages.
“hepcidin induces iron accumulation in macrophages”
From Hepcidin and Host Defense against Infectious Diseases (2015) · cites this paper as [40]
Hepcidin may be detrimental in host defense against pathogens that occupy the intracellular niche.
“may be detrimental in defense against pathogens that occupy this intracellular niche”
From Hepcidin and Host Defense against Infectious Diseases (2015) · cites this paper as [40]
In intramacrophage infections (S. Typhimurium, M. tuberculosis, M. avium), hepcidin is detrimental by promoting sequestration of iron in macrophages.
“Detrimental, by promoting sequestration of iron in macrophages”
From Hepcidin and Host Defense against Infectious Diseases (2015) · cites this paper as [40]
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- Authors
- Nairz, M., Theurl, I., Schroll, A., Theurl, M., Fritsche, G., Lindner, E., Seifert, M., Crouch, M.-L. V., Hantke, K., Akira, S., Fang, F. C., & Weiss, G.
- Affiliations
- Departments of Internal Medicine I, Clinical Immunology and Infectious Diseases, and
- Innsbruck Medical University (AT)
- University of Washington (US)
- University of Tübingen (DE)
- The University of Osaka (JP)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2009-10-22
- Volume
- 114
- Issue
- 17
- Pages
- 3642-3651
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC2766679
- OpenAlex
- W2089836445
- Cited by
- 146
- References
- 58
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 4 · 2023: 6 · 2022: 6 · 2021: 8 · 2020: 6 · 2019: 6 · 2018: 9 · 2017: 13 · 2016: 7 · 2015: 11 · 2014: 16 · 2013: 11 · 2012: 12
- FWCI
- 8.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Austrian Science Fund (P 19664)
- National Institutes of Health (AI39557)
- National Institute of Allergy and Infectious Diseases (AI54052, AI 39557, R01AI039557, F32AI054052)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Agricultural and Biological Sciences › Food Science › Salmonella and Campylobacter epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- HFE gene, neutrophil gelatinase-associated lipocalin, Salmonella typhimurium, septicemia, iron sequestration, enterochelin, macrophages, host resistance to infection, hereditary hemochromatosis, iron metabolism
- MeSH terms
- Hemochromatosis Protein, Lipocalin-2, Acute-Phase Proteins, Animals, Bacterial Proteins, Cells, Cultured, Disease Models, Animal, Female, Iron, Macrophages, Male, Membrane Proteins, Mice, Inbred C57BL, Nitrites, Salmonella Infections, Animal, Salmonella typhimurium, Histocompatibility Antigens Class I, Oncogene Proteins, Gene Expression Regulation, Bacterial, Cytokines, Reactive Oxygen Species, Mice, Knockout, Mice, Lipocalins
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