Genetic and Dietary Iron Overload Differentially Affect the Course of Salmonella Typhimurium Infection
Open accessAbstract
Genetic and dietary forms of iron overload have distinctive clinical and pathophysiological features. HFE-associated hereditary hemochromatosis is characterized by overwhelming intestinal iron absorption, parenchymal iron deposition and macrophage iron depletion. In contrast, excessive dietary iron intake results in iron deposition in macrophages. However, the functional consequences of genetic and dietary iron overload for the control of microbes are incompletely understood. Using Hfe+/+ and Hfe-/- mice in combination with oral iron overload in a model of Salmonella enterica serovar Typhimurium infection, we found animals of either genotype to induce hepcidin antimicrobial peptide expression and hypoferremia following systemic infection in an Hfe-independent manner. As predicted, Hfe-/- mice, a model of hereditary hemochromatosis, displayed reduced spleen iron content, which translated into improved control of Salmonella replication. Salmonella adapted to the iron-poor microenvironment in the spleens of Hfe-/- mice by inducing the expression of its siderophore iron-uptake machinery. Dietary iron loading resulted in higher bacterial numbers in both WT and Hfe-/- mice, although Hfe deficiency still resulted in better pathogen control and improved survival. This suggests that Hfe deficiency may exert protective effects in addition to the control of iron availability for intracellular bacteria. Our data show that a dynamic adaptation of iron metabolism in both immune cells and microbes shapes the host-pathogen interaction in the setting of systemic Salmonella infection. Moreover, Hfe-associated iron overload and dietary iron excess result in different outcomes in infection, indicating that tissue and cellular iron distribution determines the susceptibility to infection with specific pathogens.
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Written from the paper’s full text.
TL;DR
In a mouse model of systemic Salmonella Typhimurium infection, genetic Hfe deficiency and dietary iron overload had opposite effects on pathogen control: Hfe−/− mice had iron-poor spleens, restricted bacterial iron uptake, lower organ bacterial loads, and improved survival, whereas dietary iron loading increased bacterial burdens in both genotypes. The study shows that host and bacterial iron metabolism adapt dynamically during infection and that tissue/cellular iron distribution, not just total iron, shapes susceptibility.
Key findings
- Hfe−/− mice had reduced spleen iron content and improved control of Salmonella replication; 33% of Hfe−/− mice on either iron-adequate (IA) or iron-enriched (IE) diet (3 of 9 per group) survived beyond day 10, whereas all WT mice died by day 8, with WT mice on IE diet succumbing 1–2 days earlier.
- Dietary iron overload significantly increased bacterial loads in liver and spleen at day 2 post-infection in both WT and Hfe−/− mice, but Hfe−/− mice still controlled infection better and survived longer than WT mice on the same diet (e.g., P = 0.002 for Hfe+/+ IE vs. Hfe−/− IE).
- Both Hfe+/+ and Hfe−/− mice induced Hamp expression and hypoferremia after systemic infection in an Hfe-independent manner; however, mice on an IE diet had higher serum iron and did not mount hypoferremia after infection.
- Salmonella in the iron-poor spleens of IA-fed Hfe−/− mice upregulated siderophore iron-uptake genes iroN, fepA, cirA, and iroC; this differential induction was abrogated by dietary iron overload, and Hfe−/− macrophages restricted 59Fe uptake by intracellular Salmonella from both NTBI and TBI.
Methods
- Male Hfe+/+ and Hfe−/− C57BL/6 mice, aged 20–26 weeks, were fed either a standard iron-adequate diet (180 mg Fe/kg) or an iron-enriched diet supplemented with 25 g/kg carbonyl iron for 3 weeks before and during infection, then infected intraperitoneally with 500 CFU S. Typhimurium ATCC14028 and monitored for up to 10 days.
- Bacterial loads in liver and spleen were determined on days 2 and 4 post-infection; serum iron, ferritin, tissue iron, histology, and mRNA expression of host and bacterial iron-related genes were measured, with statistical analysis by ANOVA/Tukey, two-tailed unpaired Student’s t-test, or Wilcoxon (Gehan) test for survival.
- In vitro, thioglycolate-elicited peritoneal macrophages from WT and Hfe−/− mice were infected with S. Typhimurium at MOI 10 and assayed for bacterial acquisition of 59Fe provided as NTBI or transferrin-bound iron (TBI).
Limitations
- The paper does not present a formal limitations section; the discussion acknowledges that the mechanism for the survival benefit of Hfe−/− mice beyond bacterial iron restriction is unclear and suggests that an unbiased approach such as RNA-sequencing may be required to identify it.
- Evident from the design: experiments used only male mice, a single S. Typhimurium strain (ATCC14028), intraperitoneal infection rather than the natural oral route, and limited post-infection time points (days 2 and 4 for most readouts), which may restrict generalization to other hosts, routes, strains, or infection stages.
- Evident from the text: several mechanistic claims rely on in vitro peritoneal macrophage experiments and on “data not shown” for T cell-associated cytokines, so the proposed immunoregulatory role of Hfe is not fully resolved.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 56 cited sources checked · 0 supported · 0 flagged
- Findingown data
Dmt1 and TfR1 mRNA levels are negatively affected by oral iron challenge.
“Dmt1 and TfR1 mRNA levels were negatively affected by oral iron challenge (Figures 2D,E).”
Quote in the paperNot a substantial claim - Findingown data
Increased expression of NOS2 and IL-1β in mice receiving IE diet relative to IA diet parallels increased number of bacteria isolated from spleens.
“Increased expression of NOS2 and IL-1ß in mice receiving an IE diet relative to those receiving an IA diet paralleled the increased number of bacteria isolated from the spleens of these groups.”
Quote in the paperNot a substantial claim - Findingown data
Hfe+/+ and Hfe−/− mice on IE diet prior to and during Salmonella infection do not mount a hypoferremic response.
“and did not mount a hypoferremic response.”
Quote in the paperSubstantial claim - Findingown data
WT mice on IE diet succumbed 1-2 days earlier than WT on IA.
“but animals on an iron-enriched (IE) diet succumbed 1–2 days earlier (Figure 3A).”
Quote in the paperSubstantial claim - Findingown data
Hfe−/− mice on IE diet have only solitary lesions in the liver.
“and only solitary lesions were visible in Hfe−/− mice on an IE diet (Figure 4A).”
Quote in the paperNot a substantial claim
- Findingown data
IE diet results in hepatic iron accumulation.
“and the IE diet resulted in hepatic iron accumulation (Figure 1D).”
Quote in the paperSubstantial claim - Findingown data
Splenic LcnR expression is significantly reduced following Salmonella infection.
“Splenic Lcn2 receptor (LcnR) expression was significantly reduced following Salmonella infection (Figure 2F)”
Quote in the paperNot a substantial claim - Findingown data
Both Hfe+/+ and Hfe−/− mice respond to systemic Salmonella infection with reduction of serum iron (hypoferremia).
“Both Hfe+/+ and Hfe−/− responded to systemic infection with a reduction of serum iron concentrations (hypoferremia) (Figure 1A).”
Quote in the paperSubstantial claim - Findingown data
Dietary iron overload significantly increases bacterial load in liver and spleen in WT and Hfe−/− mice 2 days post-infection.
“Dietary iron overload significantly increased the bacterial load in both organs in WT mice as well as in Hfe−/− animals 2 days post-infection (Figures 3B,C).”
Quote in the paperSubstantial claim - Findingown data
Fpn1 mRNA expression increases in response to Salmonella infection.
“In contrast, Fpn1 mRNA expression increased in response to Salmonella infection”
Quote in the paperSubstantial claim - Findingown data
Splenic mRNA levels of TNF, IL-1β, IL-6, Nos2, and p47 phox are not affected by Hfe genotype.
“Splenic mRNA levels of TNF, IL-1ß, IL-6, Nos2, and the p47 subunit of the NADPH oxidase (phox) were not affected by the Hfe-genotype (Figures 5A–E).”
Quote in the paperSubstantial claim - Findingown data
Concurrent Salmonella infection reverts Dmt1 expression to basal levels.
“Concurrent Salmonella infection reverted Dmt1 expression to basal levels”
Quote in the paperNot a substantial claim - Findingown data
Under control conditions, Hfe−/− mice fed an iron-adequate diet show elevated serum ferritin compared to Hfe+/+ controls.
“As predicted, under control conditions Hfe−/− mice fed an iron-adequate (IA) diet showed elevated serum iron and serum ferritin (FT) levels as compared to Hfe+/+ controls.”
Quote in the paperNot a substantial claim - Findingown data
Serum iron levels increase upon dietary iron challenge independent of Hfe genotype.
“Of interest, serum iron levels increased upon dietary iron challenge independent of the Hfe genotype, as Hfe−/− and congenic Hfe+/+ mice displayed comparable serum iron levels on an IE diet.”
Quote in the paperSubstantial claim - Findingown data
Hfe−/− mice on IA diet have hardly any microabscesses in the liver.
“In contrast, hardly any microabscesses were observed in the livers of Hfe−/− mice on an IA diet”
Quote in the paperSubstantial claim - Findingown data
Serum ferritin levels are dramatically increased during dietary iron overload.
“Serum FT levels were dramatically increased during dietary iron overload”
Quote in the paperSubstantial claim - Findingown data
Fpn1 mRNA expression is not affected by dietary iron overload or Hfe genotype.
“but was not affected by dietary iron overload or Hfe genotype (Figure 2C).”
Quote in the paperNot a substantial claim - Findingown data
Dietary iron loading results in higher bacterial numbers in both WT and Hfe−/− mice.
“Dietary iron loading resulted in higher bacterial numbers in both WT and Hfe−/− mice”
Quote in the paperSubstantial claim - Findingown data
Under control conditions, Hfe−/− mice fed an iron-adequate diet show elevated serum iron compared to Hfe+/+ controls.
“As predicted, under control conditions Hfe−/− mice fed an iron-adequate (IA) diet showed elevated serum iron and serum ferritin (FT) levels as compared to Hfe+/+ controls.”
Quote in the paperSubstantial claim - Findingown data
Lcn2 mRNA expression in the spleen is higher in Hfe−/− compared to WT mice.
“and Lcn2 mRNA expression in the spleen was higher in Hfe−/− as compared to congenic WT mice (Figure 2G).”
Quote in the paperNot a substantial claim - Findingown data
Hfe−/− mice have elevated total iron content in the liver.
“As expected, Hfe−/− mice had an elevated total iron content in the liver”
Quote in the paperSubstantial claim - Findingown data
Hfe−/− mice have improved control of Salmonella replication.
“which translated into improved control of Salmonella replication.”
Quote in the paperSubstantial claim - Findingown data
No differential induction of bacterial iron genes is observed when WT and Hfe−/− mice are on IE diet.
“Notably, no differential induction of bacterial iron genes was observed when WT and Hfe−/− mice were on an IE diet, which resulted in splenic iron overload.”
Quote in the paperSubstantial claim - Findingown data
Salmonella infection causes a small yet significant reduction in spleen iron.
“Salmonella infection caused a small yet significant reduction.”
Quote in the paperSubstantial claim - Findingown data
Uptake of host-derived 59Fe by intracellular Salmonella, provided as NTBI or TBI, is reduced in Hfe−/− peritoneal macrophages infected in vitro relative to WT macrophages.
“we observed that the uptake of host derived 59Fe by intracellular Salmonella, provided as NTBI or TBI, was reduced in Hfe−/− peritoneal macrophages infected in vitro relative to congenic WT macrophages (Figures 7A,B).”
Quote in the paperSubstantial claim - Findingown data
Hfe−/− mice have reduced total iron content in the spleen compared to Hfe+/+ mice.
“Hfe−/− mice had reduced total iron content in the spleen is comparison to Hfe+/+ mice (Figure 2A).”
Quote in the paperNot a substantial claim - Findingown data
WT mice on IE diet exhibit hepatic macroabscesses.
“WT mice on an IE diet also exhibited hepatic macroabscesses.”
Quote in the paperNot a substantial claim - Findingown data
Hfe+/+ and Hfe−/− mice induce Hamp expression following systemic Salmonella infection in an Hfe-independent manner.
“we found animals of either genotype to induce hepcidin antimicrobial peptide expression and hypoferremia following systemic infection in an Hfe-independent manner.”
Quote in the paperSubstantial claim - Findingown data
TfR1 expression remains suppressed during concurrent Salmonella infection.
“while TfR1 expression remained suppressed.”
Quote in the paperNot a substantial claim - Findingown data
Induced Hamp expression in response to infection or dietary iron overload remains intact in Hfe−/− mice compared to WT littermates.
“the induced Hamp expression in response to infection or dietary iron overload remained intact in Hfe−/− mice compared to WT littermates (Figure 1C).”
Quote in the paperNot a substantial claim - Findingown data
All WT mice died by day 8 of infection independent of dietary iron content.
“All WT mice died by day 8 of infection independent of their dietary iron content”
Quote in the paperSubstantial claim - Findingown data
By day 4, Hfe−/− mice fed IE diet control microbial replication as efficiently as WT littermates on IA diet.
“By day 4 of infection, Hfe−/− mice fed an IE diet controlled microbial replication as efficiently as their WT littermates maintained on an IA diet (Supplementary Figures 3A,B).”
Quote in the paperSubstantial claim - Findingown data
Expression of FeoB and SitB is not substantially affected by Hfe status of host.
“In contrast, expression of FeoB (Figure 6E) and SitB (Figure 6F) were not substantially affected by the Hfe status of the host.”
Quote in the paperNot a substantial claim - Findingown data
Hfe+/+ and Hfe−/− mice on IE diet prior to and during Salmonella infection have higher serum iron levels than uninfected animals on IE diet.
“Intriguingly, Hfe+/+ and Hfe−/− mice maintained on an IE diet prior to and during Salmonella infection had even higher serum iron levels as compared to uninfected animals on an IE diet”
Quote in the paperSubstantial claim - Findingown data
Hfe+/+ and Hfe−/− mice develop hypoferremia following systemic Salmonella infection in an Hfe-independent manner.
“we found animals of either genotype to induce hepcidin antimicrobial peptide expression and hypoferremia following systemic infection in an Hfe-independent manner.”
Quote in the paperSubstantial claim - Findingown data
Salmonella adapted to the iron-poor microenvironment in the spleens of Hfe−/− mice by inducing expression of its siderophore iron-uptake machinery.
“Salmonella adapted to the iron-poor microenvironment in the spleens of Hfe−/− mice by inducing the expression of its siderophore iron-uptake machinery.”
Quote in the paperSubstantial claim - Findingown data
Dietary iron challenge results in an increase in spleen iron levels.
“Whereas, dietary iron challenge resulted in an increase in spleen iron levels”
Quote in the paperSubstantial claim - Findingown data
Multiple genes involved in iron uptake (iroN, fepA, cirA, iroC) are expressed at higher levels in spleens of Hfe−/− mice on IA diet compared to WT mice on same diet.
“We found that multiple genes involved in iron uptake were expressed at higher levels in the spleens of Hfe−/− mice on an IA diet as compared to the spleens of WT mice receiving the same diet. These genes encoded outer membrane siderophore receptors IroN, FepA, and CirA, as well as the siderophore exporter IroC (Figures 6A–D).”
Quote in the paperSubstantial claim - Findingown data
Only Hfe−/− mice on IA diet have relatively normal spleen size.
“Only Hfe−/− mice on an IA diet had a relatively normal spleen size (Figure 4B).”
Quote in the paperSubstantial claim - Findingown data
WT mice on IA diet have microabscesses in the liver, partly confluent.
“WT mice on an IA diet had microabscesses in the liver, which were partly confluent.”
Quote in the paperNot a substantial claim - Findingown data
33% of Hfe−/− mice on IA or IE diet survived beyond day 10.
“Of note, 33% of Hfe−/− mice on an iron-adequate (IA) or iron-enriched (IE) diet (3 of 9 mice in each group) survived the infection beyond day 10 of the observation period.”
Quote in the paperSubstantial claim - Findingown data
Hfe−/− mice display reduced spleen iron content.
“Hfe−/− mice, a model of hereditary hemochromatosis, displayed reduced spleen iron content”
Quote in the paperSubstantial claim - Findingown data
Salmonella infection has minimal stimulatory effect on serum ferritin levels.
“whereas the stimulatory effect of Salmonella infection on serum FT levels was minimal (Figure 1B).”
Quote in the paperNot a substantial claim - Findingreasoning
The Hfe mutation renders the host more resistant to infections with the intracellular pathogen S. Typhimurium.
“which renders the host more resistant to infections with the intracellular pathogen S. Typhimurium.”
Quote in the paperSubstantial claim - Findingown data
Lcn2 was expressed at higher levels in Hfe−/− mice.
“Given that Lcn2 was expressed at higher levels in Hfe−/− mice”
Quote in the paperSubstantial claim - Findingown data
Oral iron overload in setting of Hfe deficiency results in intermediate pathogen numbers in spleen and liver on days 2 and 4 of infection.
“Of note, oral iron overload in the setting of Hfe deficiency resulted in intermediate pathogen numbers in spleen and liver on days 2 and 4 of infection.”
Quote in the paperSubstantial claim - Findingown data
Survival of Hfe−/− mice over 10 day period is not affected by dietary iron.
“In contrast, the survival of Hfe−/− mice over a 10 day period was not affected by dietary iron.”
Quote in the paperSubstantial claim - Findingown data
Hfe is not required for the induction of hypoferremia in infected animals on an iron-replete diet.
“We also demonstrate that Hfe is not required for the induction of hypoferremia in infected animals on an iron-replete diet.”
Quote in the paperSubstantial claim - Findingcitation
TNF, IL-6, and Nos2 were not observed to be differentially expressed on day 2 or 4 of infection of Hfe−/− and Hfe+/+ mice.
“but these were not observed to be differentially expressed on day 2 or 4 of infection of Hfe−/− and Hfe+/+ mice (Nairz et al., 2015b).”
Quote in the paperSubstantial claim - Findingown data
The induction of siderophore-mediated iron uptake genes was specifically abrogated by dietary iron overload.
“This induction was specifically abrogated by dietary iron overload.”
Quote in the paperSubstantial claim - Findingnone given
The Hfe mutation alters the iron content of macrophages.
“Nevertheless, the Hfe mutation alters the iron content of macrophages”
Quote in the paperSubstantial claim - Findingown data
No differences in T cell-mediated pathways associated with immunity against S. Typhimurium such as IL-12, IFN-γ, IL-17, or IL-22 were observed between Hfe−/− and Hfe+/+ mice.
“nor were differences in T cell-mediated pathways associated with immunity against S. Typhimurium such as IL-12, IFN-γ, IL-17, or IL-22, observed (data not shown)”
Quote in the paperSubstantial claim - Findingcitation
Expression of innate immune genes known to mediate host defense against S. Typhimurium was not different between Hfe−/− and Hfe+/+ mice.
“However, the expression of innate immune genes known to mediate host defense against S. Typhimurium was not different between Hfe−/− and Hfe+/+ mice”
Quote in the paperSubstantial claim - Findingown data
S. Typhimurium expressed genes required for siderophore-mediated iron uptake in vivo in the iron-poor spleens of Hfe−/− mice.
“S. Typhimurium expressed genes required for siderophore-mediated iron uptake in vivo in the iron-poor spleens of Hfe−/− mice.”
Quote in the paperSubstantial claim - Premisecitation
In Salmonella infections, macrophages constitute an important habitat for pathogen replication and persistence.
“In infections with the intracellular bacterium Salmonella enterica serovar Typhimurium, macrophages constitute an important habitat for pathogen replication and persistence (Malik-Kale et al., 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Malik-Kale et al., 2011 source
Not checked in the free run.
- Premisecitation
Macrophage iron overload is associated with inhibition of IFN-γ-driven antimicrobial immune effector pathways such as Nos2 expression, resulting in impaired control of intracellular microbes.
“On one hand, macrophage iron overload is associated with the inhibition of IFN-γ-driven antimicrobial immune effector pathways such as nitric oxide synthase 2 (Nos2) expression, resulting in impaired control of intracellular microbes (Weiss et al., 1994; Mencacci et al., 1997; Oexle et al., 2003).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Inflammation-driven Hamp induction causes iron sequestration within the mononuclear phagocyte system, limiting iron availability for extracellular pathogens.
“Inflammation-driven Hamp induction thus causes iron sequestration within the mononuclear phagocyte system (MPS), which limits iron availability for extracellular pathogens (Bridle et al., 2003; Ludwiczek et al., 2003; Ganz, 2005; Theurl et al., 2008a).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Salmonella Typhimurium needs sufficient access to host iron resources as a prerequisite for replication and virulence.
“Salmonella Typhimurium, a facultative intracellular microbe, needs to gain sufficient access to host iron resources as a prerequisite for replication and virulence (Leung and Finlay, 1991; Vazquez-Torres et al., 1999).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Leung and Finlay, 1991
Not checked in the free run.
- cites Vazquez-Torres et al., 1999 source
Not checked in the free run.
- Interpretationreasoning
Hfe deficiency may exert protective effects in addition to the control of iron availability for intracellular bacteria.
“This suggests that Hfe deficiency may exert protective effects in addition to the control of iron availability for intracellular bacteria.”
Quote in the paperSubstantial claim - Interpretationown data
Hfe-associated iron overload and dietary iron excess result in different outcomes in infection.
“Moreover, Hfe-associated iron overload and dietary iron excess result in different outcomes in infection”
Quote in the paperSubstantial claim - Interpretationown data
Tissue and cellular iron distribution determines susceptibility to infection with specific pathogens.
“indicating that tissue and cellular iron distribution determines the susceptibility to infection with specific pathogens.”
Quote in the paperSubstantial claim - Interpretationown data
A dynamic adaptation of iron metabolism in both immune cells and microbes shapes the host-pathogen interaction in systemic Salmonella infection.
“Our data show that a dynamic adaptation of iron metabolism in both immune cells and microbes shapes the host-pathogen interaction in the setting of systemic Salmonella infection.”
Quote in the paperSubstantial claim - Premisecitation
All three pathways of bacterial iron uptake are linked to Salmonella virulence.
“All three pathways of bacterial iron uptake are linked to Salmonella virulence (Tsolis et al., 1996; Janakiraman and Slauch, 2000; Boyer et al., 2002; Crouch et al., 2008; Kim et al., 2013).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation
Lcn2 chemoattraction is unlikely to account for a survival difference beyond day 3 of infection.
“but this is unlikely to account for a survival difference beyond day 3 of infection (Schroll et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Schroll et al., 2012 source
Not checked in the free run.
- Interpretationown data
Genetic and dietary iron overload have differential effects on the course of infection.
“and the differential effects of genetic and dietary iron overload.”
Quote in the paperSubstantial claim - Interpretationown data
Macrophage iron homeostasis plays a central role in the outcome of infections with iron-dependent intracellular microbes.
“In summary, the present study highlights the central role of macrophage iron homeostasis in the outcome of infections with iron-dependent intracellular microbes”
Quote in the paperSubstantial claim - Interpretationcitation
Selective pressure imposed by intracellular pathogens may have contributed to the evolutionary conservation of the HFE C282Y mutation, accounting for its high allelic frequency in Caucasians.
“The selective pressure imposed by intracellular pathogens may have contributed to the evolutionary conservation of the HFE C282Y mutation, accounting for its high allelic frequency in Caucasians (Datz et al., 1998; Moalem et al., 2004).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationcitation
The paper's data on upregulation of bacterial iron uptake genes are in line with the specific induction of iron import mechanisms reported for Neisseria gonorrhoeae residing within human monocytes.
“Our data on the upregulation of bacterial iron uptake genes are further in line with the specific induction of iron import mechanisms reported for Neisseria gonorrhoeae residing within human monocytes (Zughaier et al., 2014).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zughaier et al., 2014 source
Not checked in the free run.
- Interpretationreasoning
In the later stages of Salmonella infection, Hfe plays an immunoregulatory function that is independent of its effect on bacterial iron-restriction.
“Albeit somewhat unexpected, these findings suggest that in the later stages of Salmonella infection, Hfe plays an immunoregulatory function that is independent of its effect on bacterial iron-restriction.”
Quote in the paperSubstantial claim - Interpretationown data
Hfe deficiency spares the myeloid compartment from iron.
“In contrast, Hfe deficiency spares the myeloid compartment from iron.”
Quote in the paperSubstantial claim - Interpretationreasoning
Phenotypes observed in our studies cannot be attributed to Slc11a1.
“Therefore, the phenotypes observed in our studies cannot be attributed to this transporter.”
Quote in the paperSubstantial claim- Rests on an assumption: C57BL/6 mice carry two dysfunctional Slc11a1 alleles.
- Interpretationown data
Genetic (Hfe-associated) and dietary iron overload have different effects on macrophage iron content.
“Our models of genetic (i.e., Hfe-associated) and dietary iron overload had different effects on macrophage iron content.”
Quote in the paperSubstantial claim - Interpretationcitation
Both host myeloid cells and facultatively intracellular bacteria actively compete for iron as an essential nutrient.
“Both studies thus support the concept that both host myeloid cells and facultatively intracellular bacteria actively compete for iron as essential nutrient.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zughaier et al., 2014 source
Not checked in the free run.
- Interpretationcitation
Our findings are unlikely to be specific for infections with S. Typhimurium but are also relevant to other iron-dependent intracellular pathogens such as Chlamydia, Legionella, Listeria, Mycobacterium, and Leishmania.
“Moreover, our findings are unlikely to be specific for infections with S. Typhimurium but are also relevant to other iron-dependent intracellular pathogens such as Chlamydia, Legionella and Listeria (Paradkar et al., 2008; Bellmann-Weiler et al., 2010, 2013; Haschka et al., 2015), as well as Mycobacterium and Leishmania.”
Quote in the paperNot a substantial claim0 of 3 sources checked
- May combine two claims. 12
- Classified as probably not a substantial claim. 13
May combine two claims.
Findingown dataHfe deficiency results in better pathogen control and improved survival.
“although Hfe deficiency still resulted in better pathogen control and improved survival.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBoth the host and the microbe adapt their iron metabolism during infection.
“A central and novel finding of our study is that both the host and the microbe adapt their iron metabolism during infection.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMacrophages lacking HFE display an iron-poor phenotype attributed to enhanced iron export.
“Of note, macrophages lacking HFE display an iron-poor phenotype which has been attributed to enhanced iron export (Cairo et al., 1997; Drakesmith et al., 2002; Wang et al., 2003).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationMacrophage iron homeostasis is an important determinant of disease outcome because many bacteria depend on sufficient iron for growth and pathogenicity.
“Because many bacteria are highly dependent on a sufficient supply of iron for their growth and pathogenicity, macrophage iron homeostasis is an important determinant of disease outcome (Nairz et al., 2014).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Nairz et al., 2014 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHFE mutations, especially the homozygous C282Y substitution, result in type I hereditary hemochromatosis.
“HFE mutations, especially the homozygous C282Y substitution, result in type I (AKA classical) hereditary hemochromatosis (HH) (Camaschella et al., 2002; Pietrangelo, 2004; Weiss, 2010)”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationHamp controls iron homeostasis by binding Fpn1, triggering its internalization, degradation, and blockade of iron efflux from duodenal enterocytes and macrophages.
“Hamp controls iron homeostasis upon binding Fpn1, which triggers Fpn1 internalization, degradation (Nemeth et al., 2004b) and blockade of iron efflux from duodenal enterocytes and macrophages, which recycle iron from senescent erythrocytes.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Nemeth et al., 2004b
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationHFE encodes an atypical MHC class I molecule that plays a major role in regulation of iron homeostasis under basal conditions.
“HFE encodes an atypical MHC class I molecule which plays a major role in the regulation of iron homeostasis under basal conditions (Feder et al., 1996; Ludwiczek et al., 2004).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationHH is characterized by reduced serum Hamp and increased duodenal absorption of iron via Dmt1 and Fpn1 despite progressive iron overload in parenchymal organs including liver, pancreas, and heart.
“HH is characterized by reduced serum levels of the antimicrobial peptide Hamp (hepcidin) and increased duodenal absorption of iron via divalent metal transporter 1 (Dmt1) and ferroportin 1 (Fpn1) despite progressive iron overload in parenchymal organs including the liver, pancreas, and heart (Zoller et al., 1999, 2001; Bridle et al., 2003; Pietrangelo, 2004; Bardou-Jacquet et al., 2013).”
Quote in the paperNot a substantial claim0 of 3 sources checkedClassified as probably not a substantial claim.
PremisecitationSalmonella Typhimurium causes a systemic disease in mice characterized by tropism for and replication within professional phagocytes.
“Salmonella Typhimurium causes a systemic disease in mice characterized by a tropism for and replication within professional phagocytes (Richter-Dahlfors et al., 1997; Coburn et al., 2007).”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLcn2 captures iron-laden bacterial siderophores.
“In its best characterized function, Lcn2 captures iron-laden bacterial siderophores, small molecules that are enzymatically synthesized and actively secreted by many microbes to bind ferric iron with extraordinarily high affinity (Bachman et al., 2009).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Bachman et al., 2009 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationUpon neutralization of siderophores, Lcn2 contributes to innate resistance against enterobacteriaceae, mycobacteria, and Bacillus anthracis by limiting their access to iron.
“Upon neutralization of these siderophores, Lcn2 contributes to innate resistance against a range of pathogenic bacteria including enterobacteriaceae, mycobacteria and Bacillus anthracis by limiting their access to iron (Flo et al., 2004; Berger et al., 2006).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSalmonella synthesizes catecholate-type siderophores such as enterochelin and salmochelins to capture and internalize ferric iron via siderophore receptors.
“Salmonella synthesizes catecholate-type siderophores such as enterochelin and salmochelins to capture and internalize ferric iron via siderophore receptors (Bäumler et al., 1998; Rabsch et al., 2003; Fischbach et al., 2005).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
InterpretationcitationIn 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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Nairz et al., 2009 source
Not checked in the free run.
May combine two claims.
Interpretationown dataHfe−/− mice with dietary iron overload remain more resistant to Salmonella infection than WT mice receiving same diet, with reduced organ loads and increased survival despite alleviation of bacterial iron-deprivation by dietary iron supplementation as measured by siderophore gene expression.
“Hfe−/− mice with dietary iron overload remain more resistant to Salmonella infection than WT mice receiving the same diet, with reduced organ loads and increased survival (Figure 3) despite the alleviation of bacterial iron-deprivation by dietary iron supplementation as measured by siderophore gene expression (Figure 6).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe mechanism by which Hfe-deficient macrophages restrict iron to Salmonella is independent of Dmt1 and TfR1 and may be attributable to differential iron turnover or efflux.
“This suggests that the underlying mechanism is independent of Dmt1 and TfR1 and may be attributable to differential iron turnover or efflux.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationHfe deficiency results in reduced Hamp production and increased serum iron levels.
“Hfe deficiency results in reduced Hamp production and increased serum iron levels (Pietrangelo, 2004).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Pietrangelo, 2004 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLcn2 is a chemoattractant for neutrophils.
“Lcn2 is a chemoattractant for neutrophils”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Schroll et al., 2012 source
Not checked in the free run.
May combine two claims.
InterpretationcitationBoth local and systemic availability of iron within the mammalian host affect infection outcome.
“The data presented herein suggest that both the local and systemic availability of iron within the mammalian host affect infection outcome (Nairz et al., 2015a).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Nairz et al., 2015a
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationIron is an essential nutrient central in interplay of host and pathogen.
“Iron is one of the essential nutrients that hold a central position in the interplay of host and pathogen (Weinberg, 1974; Schaible and Kaufmann, 2005; Skaar, 2009; Nairz et al., 2010; Drakesmith and Prentice, 2012; Ganz and Nemeth, 2015; Soares and Weiss, 2015).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationHamp and Fpn1 are primary mediators of hypoferremia and influence Salmonella-host interactions.
“Hamp and its receptor Fpn1 are primary mediators of the hypoferremia, and thereby influence Salmonella-host interactions (Nairz et al., 2013; Kim et al., 2014; Armitage et al., 2016).”
Quote in the paperSubstantial claim0 of 3 sources checkedClassified as probably not a substantial claim.
PremisecitationBacterial iron homeostasis and virulence gene expression are cross-regulated.
“This possibility is supported by the known cross-regulation of bacterial iron homeostasis and virulence gene expression (Zaharik et al., 2002).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zaharik et al., 2002 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSlc11a1 influences the course of infection with S. Typhimurium and certain species of Mycobacterium and Leishmania.
“Slc11a1 (also known as Nramp1) has long been known to influence the course of infection with S. Typhimurium and certain species of Mycobacterium and Leishmania (Vidal et al., 1993; Atkinson et al., 1997; Blackwell et al., 2003).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLcn2 promotes macrophage antibacterial effector mechanisms including TNF, IL-6, and Nos2.
“Furthermore, Lcn2 promotes macrophage antibacterial effector mechanisms including TNF, IL-6, and Nos2”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Nairz et al., 2015b
Not checked in the free run.
The paper relies on this without support.
Excessive dietary iron intake results in iron deposition in macrophages.
“In contrast, excessive dietary iron intake results in iron deposition in macrophages.”
The paper relies on this without support.
C57BL/6 mice carry two dysfunctional Slc11a1 alleles.
“We used C57BL/6 mice for our studies, which carry two dysfunctional Slc11a1 alleles.”
The paper relies on this without support.
Long-term oral iron overload results in increased iron content in virtually all cell types expressing Dmt1 and/or TfR1.
“Long-term oral iron overload results in increased iron content in virtually all cell types expressing Dmt1 and/or TfR1.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 [88]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Conflicting survival-analysis tests
MajorThe methods specify the Wilcoxon (Gehan) statistic for survival comparisons, but the Figure 3 caption says the survival curves were compared by a log-rank test.
“For comparison of survival between subgroups, the Wilcoxon (Gehan) statistic was used.”
“Data are depicted as Kaplan-Meier curves and were compared by log rank test.”
Conflicting durations of 59Fe exposure
MajorThe methods say cells were incubated for an additional 8 hours after 59Fe was added, whereas the Figure 7 caption says they were exposed to 59Fe for 24 hours.
“After the addition of 5 μM 59Fe as citrate (NTBI) or loaded onto human apo-transferrin (TBI; Sigma), cells were incubated for an additional 8 h.”
“WT and Hfe−/− macrophages were infected with S. Typhimurium and exposed to 59Fe for 24 h.”
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BackgroundThe Transferrin Receptor Modulates Hfe-Dependent Regulation of Hepcidin Expression
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Intravenous Iron in Patients Undergoing Maintenance Hemodialysis
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“In experimental studies, iron-enriched diets conferred protection against certain infections, including Helicobacter pylori and Mycobacterium bovis (Agoro et al., 2017; Beckett et al., 2016) but exacerbated infections with Salmonella (Nairz et al., 2017).”
InfluentialIron and innate antimicrobial immunity-depriving the pathogen, defending the host
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Dietary iron loading negatively affects liver mitochondrial function
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Self-citationEffect of Serum Ferritin on the Prognosis of Patients with Sepsis: Data from the MIMIC-IV Database
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A Salmonella subset exploits erythrophagocytosis to subvert SLC11A1-imposed iron deprivation
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Parenteral iron—Does it increase infection risk?
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Iron in Cell Metabolism and Disease
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Role of iron in the treatment of sepsis
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Famine, tea, and bread in Ireland: C282Y and modern human microevolution
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Iron homeostasis and cytokine responses in Gabonese children with febrile illness
Mayr, W., Ndong, P. E., ALABI, A. K., Kabwende, A. L., Weiß, G., & Agnandji, S. T. (2025) · Communications Medicine · doi:10.1038/s43856-025-00988-3
Wang, Y., Liu, P., Zhu, C., Shen, D., Zhang, M., Kou, R., Lan, B., Zhu, H., Huang, J., Zhao, C., et al. (2026) · Small · doi:10.1002/smll.76147
Iron homeostasis at the interface of nutrition, infection, and iron supplementation
Mert, Ö., Saday, S., & Temel, A. (2026) · Frontiers in Nutrition · doi:10.3389/fnut.2026.1943495
- Authors
- Nairz, M., Schroll, A., Haschka, D., Dichtl, S., Tymoszuk, P., Demetz, E., Moser, P., Haas, H., Fang, F. C., Theurl, I., & Weiss, G.
- Affiliations
- Innsbruck Medical University (AT)
- University of Washington (US)
- Corresponding author
- Nairz, Manfred
- ORCID
- Venue
- Frontiers in Cellular and Infection Microbiology
- Publisher
- Frontiers Media SA
- Published
- 2017-04-11
- Volume
- 7
- Pages
- 110-110
- ISSN
- 2235-2988 (ISSN-L)
- PMC
- PMC5387078
- OpenAlex
- W2606065039
- Semantic Scholar
- 8eb3c405b27204abcb63e499012b0ac8c72be81e
- Cited by
- 46
- References
- 122
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 4 · 2023: 2 · 2022: 7 · 2021: 3 · 2020: 3 · 2019: 8 · 2018: 6 · 2017: 3
- FWCI
- 4.21
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Cellular and Infection Microbiology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Austrian Science Fund (W1253-Doctoral college-HOROS, TRP-188)
- National Institutes of Health (AI118962)
- 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
- hereditary hemochromatosis, HFE gene, iron overload, Salmonella typhimurium, systemic bacterial infection, hepcidin, hypoferremia, host-pathogen interaction, iron metabolism, macrophages
- MeSH terms
- Hemochromatosis Protein, Animals, Disease Models, Animal, Salmonella Infections, Salmonella typhimurium, Mice, Knockout, Iron Overload, Iron, Dietary, Mice, Host-Pathogen Interactions
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