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Cited by 227Iron Metabolism and DisordersVibrio bacteria research studiesHemoglobin structure and function

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

Open access
Arezes, João, Jung, Grace, Gabayan, Victoria, Valore, Erika, Ruchala, Piotr, Gulig, Paul A., Ganz, Tomas, Nemeth, Elizabeta +1 more·2015·Cell Host & Microbe
DOI 10.1016/j.chom.2014.12.001PMC PMC4296238
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Abstract

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.

Integrity signals

Registry

Crossref · 10.1016/j.chom.2014.12.001

Cites

47 of 47 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

9 of 39 cited sources checked · 3 supported · 0 flagged · accuracy not yet measured

  • Findingown data

    Giving hepcidin agonists rescues hepcidin-deficient mice from death from V. vulnificus infection regardless of initial iron levels.

    “rescues these mice from death, regardless of initial iron levels”
    • Also stated in: § Minihepcidin PR73 protects against mortality from infections with Vibrio vulnificus · plain
      “mice treated with minihepcidin survived, regardless of their iron load and regardless of the number of bacteria administered”
    Quote in the paperSubstantial claim
  • Findingown data

    In mice infected with V. vulnificus, hepcidin deficiency decreases survival under both iron-depleted and iron-loaded dietary conditions.

    “hepcidin deficiency results in increased bacteremia and decreased survival of infected mice”
    • Also stated in: § Hepcidin is required for resistance to V. vulnificus infection · plain
      “In both iron-depleted (Figure 1A) and iron-loaded (Figure 1B) conditions Hamp1−/− mice were significantly more susceptible than WT mice”
    Quote in the paperSubstantial claim
  • Findingown data

    Adding deferiprone to iron-rich serum prevents V. vulnificus growth.

    “Conversely, addition of the synthetic iron chelator deferiprone to iron-rich serum prevented bacterial growth.”
    Quote in the paperSubstantial claim
  • Findingown data

    Giving hepcidin agonists to hepcidin-deficient mice decreases bacterial loads.

    “decreases bacterial loads”
    • Also stated in: § Minihepcidin PR73 protects against mortality from infections with Vibrio vulnificus · plain
      “minihepcidin treatment resulted in decreased numbers of bacteria in blood and liver of both iron-depleted and iron-loaded mice”
    Quote in the paperSubstantial claim
  • Findingown data

    Hamp1−/− mice infected with V. vulnificus show dilated venules in skin and hepatic circulation compared with saline-treated mice.

    “The venules in the skin and hepatic circulation of infected mice were greatly dilated compared with saline-treated mice (Figure 2A–D and E–H).”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 20
  • May combine two claims. 30

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Human V. vulnificus infections and their laboratory models often terminate in septic shock.

    “Human infections with V. vulnificus and their laboratory models often terminate in septic shock (Shan et al., 2012).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Shan et al., 2012 source

      The Materials and Methods section describes human hepatocellular carcinoma specimens and cell cultures, while the Discussion passages concern Nanog and cancer-cell experiments. Searches for “V. vulnificus septic shock” and “human infections laboratory models terminate in septic shock” found no passage about Vibrio vulnificus infections or septic shock in our copy. (LLM, conf=0.77)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Iron is required for rapid growth of V. vulnificus and lethality during infections, as previously shown in mice injected with iron-dextran.

    “Iron is thought to be required for rapid growth of V. vulnificus and lethality during infections, as was previously demonstrated in mice injected with iron-dextran (Starks et al., 2000; Wright et al., 1981).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Starks et al., 2000 source

      The section on subcutaneous inoculation of non-iron-dextran-treated mice reports that iron-dextran treatment allowed small inocula to cause lethal infection within 18–20 hours. It also reports lethal infection without iron-dextran treatment when the inoculum was much larger. The paper supports iron treatment as strongly promoting infection, but does not demonstrate that the treatment is required for rapid growth or lethality. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites Wright et al., 1981 source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Minihepcidins are synthetic hepcidin agonists that were previously shown to bind ferroportin, cause its endocytosis and proteolysis, and prevent iron overload in hepcidin-deficient mice.

    “Minihepcidins are synthetic hepcidin agonists previously shown to bind ferroportin and induce its endocytosis and proteolysis, thus preventing iron overload in hepcidin-deficient mice (Preza et al., 2011; Ramos et al., 2012).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Preza et al., 2011 source

      The Results report that synthetic minihepcidins caused ferroportin-GFP degradation in a cellular assay and significantly reduced liver iron in hepcidin-1 knockout mice. The Discussion describes a minihepcidin–ferroportin interaction, but the Introduction attributes ferroportin endocytosis to native hepcidin; our copy does not show that minihepcidins themselves induced endocytosis. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Ramos et al., 2012 source

      The Introduction (page not provided) describes minihepcidins as hepcidin-derived agonists, and the Results report minihepcidin-induced loss of ferroportin. The paper also reports prevention of iron loading in hepcidin-deficient mice. However, its explicit statement that binding triggers ferroportin endocytosis and proteolysis concerns hepcidin, not a demonstrated action of minihepcidins. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    IL-6 is an inflammatory signal that induces hepatic hepcidin expression via the JAK/STAT3 pathway.

    “IL-6 acts as an inflammatory signal that triggers hepcidin expression in the liver through the JAK/STAT3 pathway (Nemeth et al., 2004a; Verga Falzacappa et al., 2007; Wrighting and Andrews, 2006).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Nemeth et al., 2004a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Verga Falzacappa et al., 2007 source
    • cites Wrighting and Andrews, 2006 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Hepcidin deficiency changes tissue iron distribution and depletes macrophages of iron, which could affect innate immune signaling.

    “Hepcidin deficiency results in altered tissue iron distribution and iron-depleted macrophages, and this could potentially affect innate immune signaling (Oexle et al., 2003; Wang et al., 2009).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Oexle et al., 2003 source
    • cites Wang et al., 2009 source

  • May combine two claims.

    Premisecitation

    Minihepcidin PR73 is a synthetic hepcidin agonist with greater potency and longer lasting effect than full-length hepcidin.

    “we tested the therapeutic effect of minihepcidin PR73 (a synthetic hepcidin agonist, Figure S5) in Hamp1−/− mice. We used minihepcidin because it has greater potency and longer lasting effect than full-length hepcidin (Ramos et al., 2012).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Ramos et al., 2012 source

      The Abstract describes minihepcidins as hepcidin agonists and reports superior potency and duration of action for PR65 compared with natural hepcidin. The Methods and Results also identify PR65—not PR73—as the peptide studied. The cited paper therefore supports the general rationale for using a minihepcidin, but not the claim about PR73 specifically. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Hosts have evolved countermeasures to restrict iron bioavailability and starve microbes.

    “The hosts have evolved several countermeasures to restrict the bioavailability of iron and effectively starve the microbes (Ganz, 2009).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Ganz, 2009 source

  • May combine two claims.

    Premisecitation

    The plasmid pGTR905 replicates only when arabinose is present, and arabinose is absent from mouse tissues.

    “The plasmid replicates only in the presence of arabinose, which is not found in mouse tissues.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Starks et al., 2006 source

      The Construction of marker plasmid pGTR902 section says that pGTR902 replicates in the presence of arabinose and does not replicate without it. The Discussion says arabinose was not present in mice at levels high enough to initiate replication, but does not claim absolute absence. The source identifies the plasmid as pGTR902, not pGTR905; page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    In liver of infected mice, no bacteria are seen but neutrophilic infiltration occurs in perivenular spaces.

    “In the liver, no bacteria were seen but there was neutrophilic infiltration in perivenular spaces (Figure S2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Giving hepcidin agonists to hepcidin-deficient mice induces hypoferremia; PR73 pretreatment produced serum iron of 3 μM in iron-depleted and 9 μM in iron-loaded mice.

    “timely administration of hepcidin agonists to hepcidin-deficient mice induces hypoferremia”
    • Also stated in: § Minihepcidin PR73 protects against mortality from infections with Vibrio vulnificus · plain
      “Administration of minihepcidin caused marked hypoferremia (3 μM in iron-depleted and 9 μM in iron-loaded mice) (Figure 5A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Under iron-loaded conditions with a large inoculum, iron-loaded mice died within 2 days while most iron-depleted mice survived.

    “Under those conditions, iron-loaded mice died within 2 days after infection while most of the iron-depleted mice still survived (Figure S1A)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Serum containing minihepcidin had only a slight bactericidal effect, too small to account for the large drop in total bacterial CFU.

    “we demonstrated that the minihepcidin-containing serum had only a slight bactericidal effect that was not sufficient to explain the dramatically lower number of total bacterial CFU.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Only WT mice, not Hamp1−/− mice, were able to generate significant hypoferremia after V. vulnificus infection.

    “Only WT but not Hamp1−/− animals were able to generate significant hypoferremia”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Hamp1−/− mice had a much smaller decrease in serum iron after infection (mean 63 μM in iron-depleted and 52 μM in iron-loaded infected mice), insufficient to affect V. vulnificus replication.

    “whereas Hamp1−/− mice had a much smaller decrease in serum iron (mean of 63 μM in iron-depleted and 52 μM in iron-loaded infected mice), insufficient to affect the replication of V. vulnificus.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Infected mice had dramatically increased serum IL-6 starting at 3 h after infection, with no differences between iron-depleted and iron-loaded mice.

    “We found dramatically increased serum concentrations of this pro-inflammatory cytokine in infected mice starting at 3 h after infection (Figure 4D), with no differences between iron-depleted and iron-loaded mice.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At 10 h after infection, serum hepcidin increased further in iron-depleted mice and stabilized at very high levels in iron-loaded mice.

    “At 10 h after infection, serum hepcidin increased further in iron-depleted mice and stabilized at very high levels in iron-loaded mice (Figure 4B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Infected mice also had similar increases in KC-GRO, IL-12p70, IL-1β, TNF-α, IL-10 and IL-2, while IFN-γ, IL-4 and IL-5 remained unchanged.

    “A similar increase was also observed for the inflammatory cytokines KC-GRO, IL-12p70, IL-1β, TNF-α, IL-10 and IL-2, while IFN-γ, IL-4 and IL-5 remained unchanged (Figure S4C).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Hepcidin loss in Hamp1−/− mice produces a particularly severe disease form and almost completely removes the hypoferremia of infection.

    “In contrast, the loss of hepcidin in Hamp1−/− mice generates a particularly severe form of the disease and it nearly completely ablates the hypoferremia of infection.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingreasoning

    Liver iron stores did not change after PR73 treatment, likely because of the short duration of the experiment (40 h).

    “Liver iron stores did not change likely because of the short duration of the experiment (40 h) (Figure 5B).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Short-term minihepcidin treatment strongly lowered serum iron while leaving liver iron stores unchanged.

    “In the current study, the short-term minihepcidin treatment robustly decreased serum iron without altering liver iron stores.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Increases in hepcidin concentrations were accompanied by a significant decrease in serum iron at 6 h and 10 h in iron-depleted mice, and a trend toward decreased serum iron in iron-loaded mice.

    “These increases in hepcidin concentrations were accompanied by a significant decrease in serum iron at 6 h and 10 h in iron-depleted mice (Figure 4C), and a trend toward decreased serum iron in iron-loaded mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    When very large inocula (10^6 and 10^7 CFU) were administered to WT mice, minihepcidins did not further protect them from lethal infection, arguing against a direct microbicidal effect of these peptides in vivo.

    “When very large inocula of V. vulnificus (106 and 107 CFU) were administered to WT mice, minihepcidins did not further protect them from lethal infection (Figure S6), arguing against a direct microbicidal effect of these peptides in vivo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    NTBI was detected only in iron-loaded Hamp1−/− mice (1.28±0.60 LPI units), not in iron-depleted Hamp1−/− mice.

    “NTBI was only detected in iron-loaded mice (1.28± 0.60 LPI units), but not in the iron-depleted group (Figure 3D)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Moderately hypoferremic sera from low-iron diet slowed V. vulnificus growth compared to iron-rich sera from high-iron diet, with >10-fold decreased T/P ratio, without affecting plasmid-containing bacteria.

    “Moderately hypoferremic sera (because of low-iron diet) slowed down Vibrio growth compared to iron-rich sera (because of high-iron diet), as shown by a more than 10-fold decreased T/P ratio (Table S2), without affecting the number of plasmid-containing bacteria (Figure 7D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Giving hepcidin agonists before or after infection to hepcidin-deficient mice increased resistance to V. vulnificus and prevented death.

    “Pointing to potential therapeutic applications, pre- or post-infection administration of hepcidin agonists to hepcidin-deficient mice increased their resistance to V. vulnificus infection and protected them from consequent mortality.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hepcidin has direct bactericidal activity in vitro only at unphysiologically high concentrations.

    “Hepcidin was also reported to have direct bactericidal activity in vitro (Krause et al., 2000; Park et al., 2001), but the effect is seen only at unphysiologically high concentrations.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Krause et al., 2000 source
    • cites Park et al., 2001 source

  • May combine two claims.

    Premisecitation

    Hepcidin binding to ferroportin triggers its degradation, decreasing iron transfer to plasma and causing hypoferremia.

    “Hepcidin binding to ferroportin triggers its degradation, resulting in decreased transfer of iron to plasma and consequently hypoferremia (Nemeth et al., 2004b).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Nemeth et al., 2004b

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationown data

    V. vulnificus can grow adequately with limited iron availability, but excess iron greatly increases its growth rate.

    “This indicates that V. vulnificus can grow adequately even with limited iron availability but that excess iron greatly increases the growth rate.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: V. vulnificus growth in ex vivo serum reflects its replication and dissemination in infected mice.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Inflammatory cytokines including IL-6 and possibly activin B stimulate hepcidin production.

    “stimulated by inflammatory cytokines including IL-6 (Nemeth et al., 2004a; Rodriguez et al., 2014) and possibly activin B (Besson-Fournier et al., 2012).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Nemeth et al., 2004a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Rodriguez et al., 2014 source
    • cites Besson-Fournier et al., 2012 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hereditary hemochromatosis is caused by deficiency of the iron-regulatory hormone hepcidin.

    “Hereditary hemochromatosis is caused by deficiency of the iron-regulatory hormone hepcidin (Ganz and Nemeth, 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ganz and Nemeth, 2011 source

  • Classified as probably not a substantial claim.

    Premisecitation

    V. vulnificus causes fulminant sepsis with mortality higher than 50% in susceptible patients with hereditary hemochromatosis and other iron overload conditions.

    “Vibrio vulnificus causes fulminant sepsis with mortality higher than 50% in susceptible patients including those with hereditary hemochromatosis and other iron overload conditions (Horseman and Surani, 2011)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Horseman and Surani, 2011 source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    V. vulnificus does not cause severe illness in healthy individuals.

    “but it does not cause severe illness in healthy individuals.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hepcidin and its fragments have microbicidal activity in vitro.

    “Since hepcidin and its fragments have microbicidal effects in vitro (Park et al., 2001)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Park et al., 2001 source

  • May combine two claims.

    Interpretationown data

    WT mice had low NTBI levels similar to iron-depleted Hamp1−/− mice, suggesting NTBI did not contribute to bacterial growth in WT mice.

    “WT mice had low NTBI levels, similar to those in iron-depleted Hamp1−/− mice, suggesting that NTBI did not contribute to bacterial growth in WT mice.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    IL-6 is thought to be the predominant stimulus for hepcidin synthesis during inflammation.

    “IL-6 is thought to be the predominant stimulus for hepcidin synthesis during inflammation (Nemeth et al., 2004a; Rodriguez et al., 2014).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Nemeth et al., 2004a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Rodriguez et al., 2014 source

  • May combine two claims.

    Interpretationown data

    Baseline transferrin-bound iron, NTBI, and reactive hypoferremia, all controlled by hepcidin, determine V. vulnificus replication and dissemination in vivo.

    “Thus, our data suggest that baseline concentrations of transferrin-bound and non-transferrin bound iron as well as reactive hypoferremia, all of which are controlled by hepcidin, determine the replication and dissemination of V. vulnificus in vivo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Plasma iron levels during infection governed both V. vulnificus growth and host death.

    “This together with studies of the effect of serum iron on V. vulnificus growth ex vivo indicated that plasma iron concentrations during the course of infection determined the growth of V. vulnificus and host mortality.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    This variability comes from genetic modifiers such as gender and environmental factors such as alcohol intake.

    “The variability is attributable to both genetic modifiers (e.g. gender) and environmental factors (e.g. alcohol intake).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Waalen et al., 2002 source

  • Classified as probably not a substantial claim.

    Premisenone given

    The growth of pathogens in hosts is critically dependent on their ability to capture and utilize iron.

    “The growth of pathogens in their hosts is critically dependent on the pathogens’ ability to capture and utilize iron.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The rapid death of susceptible humans after V. vulnificus infection implies that a comparable rapid-growth program might operate in human infections.

    “The early mortality of susceptible humans after infection with these bacteria suggests that a similar program may be activated during human infections with V. vulnificus.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Activin B also stimulates hepcidin production during inflammation through SMAD1/5/8 signaling.

    “Activin B, through SMAD1/5/8 signaling (Besson-Fournier et al., 2012), is also a stimulus for hepcidin production in response to inflammation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Besson-Fournier et al., 2012 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Group differences were tested with Student t test for normally distributed data or Mann-Whitney U test otherwise.

    “The statistical significance of differences between groups was evaluated using Student t test if data were normally distributed or Mann-Whitney U test if this condition was not met.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All animal experiments were approved by the UCLA Office of Animal Research Oversight.

    “All experiments involving animals were approved by the University of California, Los Angeles (UCLA) Office of Animal Research Oversight.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Hepcidin is important in host defense against siderophilic bacteria such as V. vulnificus by setting baseline plasma iron and producing hypoferremia after infection.

    “In summary, hepcidin plays an important role in host defense against siderophilic bacteria such as V. vulnificus by controlling baseline plasma iron concentrations and mediating hypoferremia in response to infection.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Gene expression data were normalized to β-actin.

    “Data were normalized to the expression of β-actin.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Survival differences were analyzed with Kaplan-Meier curves and the Log-Rank test.

    “Survival differences were analyzed using Kaplan-Meier survival curves and Log-Rank test.”
    Quote in the paperNot a substantial claim
46 of 46

  • The paper relies on this without support.

    The mouse model of hepcidin deficiency and V. vulnificus infection predicts infection outcomes in humans with hereditary hemochromatosis or thalassemia.

    “suggest that hepcidin agonists may improve infection outcomes in patients with hereditary hemochromatosis or thalassemia”
    “Like healthy humans, WT mice, which appropriately respond to infection by inducing endogenous hepcidin, are highly resistant to V. vulnificus infection.”

  • The paper relies on this without support.

    V. vulnificus growth in ex vivo serum reflects its replication and dissemination in infected mice.

    “we assessed bacterial growth ex vivo in sera collected from uninfected iron-loaded or iron-depleted WT animals”
    “mirroring the in vivo CFU results (Figure 5C,D)”

  • The paper relies on this without support.

    Human hereditary hemochromatosis is a well-established risk factor for lethal infection with V. vulnificus.

    “Human hereditary hemochromatosis is a well-established risk factor for lethal infection with V. vulnificus.”

  • The paper relies on this without support.

    Healthy humans do not develop severe V. vulnificus infections.

    “healthy humans do not develop severe V. vulnificus infections.”
4 of 4

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?

  • Hepcidin is critical for mouse survival in Vibrio vulnificus infection.

    “We previously showed that hepcidin is critical for mouse survival in V vulnificus infection,10”

    From Endogenous hepcidin and its agonist mediate resistance to selected infections by clearing non-transferrin-bound iron (2017) · cites this paper as [10]

  • Treatment with hepcidin agonists (minihepcidins) rescues mice infected with siderophilic bacteria by inducing hypoferraemia and redistributing iron from extracellular space into macrophages.

    “Interestingly, mice infected with siderophilic bacteria were rescued by treatment with potent hepcidin agonists (known as minihepcidins) that induced hypoferraemia. These treatments had little or no effect on iron stores but redistributed iron from the extracellular space into macrophages.”

    From Iron homeostasis in host defence and inflammation (2015) · cites this paper as [52]

  • Hepcidin-deficient mice die of sepsis within 16 hours after subcutaneous infection with V. vulnificus at doses tolerated by wild-type mice.

    “Hepcidin-deficient mice die of sepsis in less than 16 hours after subcutaneous infection with V. vulnificus at doses that are otherwise well tolerated by wild-type mice52.”

    From Iron homeostasis in host defence and inflammation (2015) · cites this paper as [52]

  • Ex vivo growth of V. vulnificus in mouse sera is greatly accelerated by adding ferric iron in amounts exceeding transferrin's binding capacity.

    “Ex vivo growth of V. vulnificus in mouse sera was greatly accelerated by the addition of ferric iron in amounts that exceeded the binding capacity of transferrin52.”

    From Iron homeostasis in host defence and inflammation (2015) · cites this paper as [52]

  • Susceptibility to death from V. vulnificus infection correlates with the presence of non-transferrin-bound iron in mouse sera and with the ability of those sera to support rapid in vitro growth of V. vulnificus.

    “Susceptibility to death from infection with V. vulnificus correlated with the presence of non-transferrin-bound iron in the mouse sera and with the ability of sera from these mice to support rapid in vitro growth of V. vulnificus.”

    From Iron homeostasis in host defence and inflammation (2015) · cites this paper as [52]

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Authors
Arezes, J., Jung, G., Gabayan, V., Valore, E., Ruchala, P., Gulig, P. A., Ganz, T., Nemeth, E., & Bulut, Y.
Affiliations
  • University of California, Los Angeles (US)
  • University of Florida (US)
Corresponding author
Ganz, Tomas
ORCID
Venue
Cell Host & Microbe
Publisher
Elsevier BV
Published
2015-01
Volume
17
Issue
1
Pages
47-57
ISSN
1931-3128 (ISSN-L)
DOI
10.1016/j.chom.2014.12.001
PMC
PMC4296238
OpenAlex
W2029441236
Semantic Scholar
083b5780917192e0f31049fe500edf9d95146cc5
Cited by
227
References
50
Citations by year
2026: 10 · 2025: 13 · 2024: 15 · 2023: 18 · 2022: 21 · 2021: 17 · 2020: 31 · 2019: 24 · 2018: 19 · 2017: 32 · 2016: 13 · 2015: 14
FWCI
20.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Host & Microbe (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Fundação para a Ciência e a Tecnologia
  • National Institutes of Health (R01 DK090554)
  • University of California, Los Angeles
  • Children's Discovery and Innovation Institute, University of California, Los Angeles
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Vibrio bacteria research studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
Keywords
hepcidin, hypoferremia, Vibrio vulnificus, hereditary hemochromatosis, iron homeostasis, host defense against infection, bacteremia, thalassemia, iron overload
MeSH terms
Animals, Defense Mechanisms, Iron, Mice, Inbred C57BL, Vibrio Infections, Bacteremia, Mice, Knockout, Vibrio vulnificus, Bacterial Load, Hepcidins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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