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Cited by 228Iron Metabolism and DisordersImmune Response and InflammationGut microbiota and health

The Iron age of host–microbe interactions

Open access
Soares, Miguel P, Weiss, Günter·2015·The EMBO Reports
DOI 10.15252/embr.201540558PMC PMC4641501
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Abstract

Microbes exert a major impact on human health and disease by either promoting or disrupting homeostasis, in the latter instance leading to the development of infectious diseases. Such disparate outcomes are driven by the ever-evolving genetic diversity of microbes and the countervailing host responses that minimize their pathogenic impact. Host defense strategies that limit microbial pathogenicity include resistance mechanisms that exert a negative impact on microbes, and disease tolerance mechanisms that sustain host homeostasis without interfering directly with microbes. While genetically distinct, these host defense strategies are functionally integrated, via mechanisms that remain incompletely defined. Here, we explore the general principles via which host adaptive responses regulating iron (Fe) metabolism impact on resistance and disease tolerance to infection.

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Written from the paper’s full text.

TL;DR

This review proposes that host iron and heme metabolism is a central, pathogen-class-specific defense axis, with distinct strategies against extracellular versus intracellular microbes. It integrates nutritional immunity, resistance, and disease tolerance through hepcidin/ferroportin, macrophage iron handling, heme oxygenase-1, ferritin, and carbon monoxide, and discusses therapeutic implications.

Key findings

  • Host responses to extracellular pathogens generally lower circulating iron by retaining iron in macrophages (hypoferremia), via hepcidin-mediated ferroportin degradation, IFN-γ/TNF effects, DMT1, lactoferrin, lipocalin-2, and hemoglobin/heme scavenging; this limits microbial iron access but can produce anemia of inflammation. Macrophages recycle about 95% of the iron needed for erythropoiesis, over 80% of bioavailable mammalian iron is heme-bound, and ferritin can store roughly 4,500 Fe²⁺ atoms per molecule.
  • Host responses to intracellular pathogens generally reduce macrophage intracellular iron and promote iron export (hyperferremia), via NRAMP1, ferroportin, Nrf2, lipocalin-2, and IRP regulation; this restricts phagosomal iron and supports IFN-γ-driven microbicidal programs.
  • Disease tolerance is supported by heme catabolism by HO-1, ferritin-mediated iron storage, and CO; these mechanisms prevent labile heme/hemoglobin toxicity, sustain erythropoiesis, and protect tissues without necessarily changing pathogen burden. In mice, HO-1/CO and ferritin H protect against severe malaria and polymicrobial sepsis; sickle hemoglobin mutations confer malaria tolerance via CO-dependent HO-1 induction. Adult humans have ~2–3 × 10¹³ red blood cells, each with ~3 × 10⁸ hemoglobin and ~1.2 × 10⁹ heme molecules.
  • Therapeutic targeting is pathogen-class dependent: Nifedipine promoted macrophage iron efflux and resistance to Salmonella in mice; hepcidin/hepcidin mimetics limited Vibrio vulnificus in mice; lactoferrin and Lcn2 have shown anti-infective effects; iron chelation results are mixed (desferrioxamine in malaria gave no overt survival benefit; desferasirox improved survival in mucormycosis mice but a small clinical trial had unfavorable outcomes).

Methods

  • Narrative review, not primary research; it synthesizes mechanistic, genetic, and pharmacological studies across host–microbe interactions and iron/heme metabolism.
  • No systematic search, dataset, or statistical analysis is described; evidence comes from cited animal models, human genetic associations, and clinical studies.
  • Main analysis is conceptual integration: it proposes pathogen class-specific regulation of iron/heme metabolism as a framework linking nutritional immunity, resistance, and disease tolerance.

Limitations

  • The paper states no formal limitations.
  • Evident from the text: as a narrative review, it lacks a systematic search strategy or quantitative synthesis, so selection and interpretation of cited evidence may reflect author perspective.
  • Evident from the text: many mechanisms and translational claims remain unresolved or untested, including whether ROS/RNS drive hepcidin-independent hypoferremia, whether HO-1 acts mainly in macrophages or parenchyma, whether mouse findings extrapolate to human co-infections, and why clinical chelation outcomes are inconsistent.

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Integrity signals

Registry

Crossref · 10.15252/embr.201540558

Cites

246 of 246 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 266 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Dietary iron supplementation exacerbates the overall mortality rate in areas endemic for infectious diseases.

    “while dietary Fe supplementation exacerbates the overall rate of mortality in areas endemic for such infectious diseases [23][24][25][26][27].”
    Quote in the paperSubstantial claim0 of 3 sources checked
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      Not checked in the free run.

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      Not checked in the free run.

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  • Premisecitation

    Microbes evolved strategies to acquire iron from hosts, commonly via siderophores that elute iron from host iron-binding proteins and other iron uptake systems.

    “Microbes evolved strategies to acquire Fe from their hosts [5][6][7]17].These share as a common denominator the expression of siderophores that elute Fe from host Fe-binding proteins [29,30] as well as other Fe uptake systems [6,31].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [5] Weinberg ED (2009) Iron availability and infection. Biochim Biophys Acta 1790: 600–605 source

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    • cites [6] Nairz M, Haschka D, Demetz E, Weiss G (2014) Iron at the interface of immunity and infection. Front Pharmacol 5: 152 source

      Not checked in the free run.

    • cites [29] Diaz‐Ochoa VE, Jellbauer S, Klaus S, Raffatellu M (2014) Transition metal ions at the crossroads of mucosal immunity and microbial pathogenesis. Front Cell Infect Microbiol 4: 2

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    • cites [30] Contreras H, Chim N, Credali A, Goulding CW (2014) Heme uptake in bacterial pathogens. Curr Opin Chem Biol 19: 34–41 source

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  • Premisecitation

    Host iron overload is associated with poor clinical outcomes in infectious diseases such as AIDS, malaria, and tuberculosis.

    “In support of this notion, host Fe overload is associated with poor clinical outcomes in a number of infectious diseases such as AIDS (i.e., co-infections resulting from HIV-driven immunodeficiency), malaria, and tuberculosis [19][20][21][22]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [19] Gordeuk VR, Delanghe JR, Langlois MR, Boelaert JR (2001) Iron status and the outcome of HIV infection: an overview. J Clin Virol 20: 111–115 source

      Not checked in the free run.

    • cites [20] Mabeza GF, Loyevsky M, Gordeuk VR, Weiss G (1999) Iron chelation therapy for malaria: a review. Pharmacol Ther 81: 53–75 source

      Not checked in the free run.

    • cites [21] McDermid JM, Hennig BJ, van der Sande M, Hill AV, Whittle HC, Jaye A, Prentice AM (2013) Host iron redistribution as a risk factor for incident tuberculosis in HIV infection: an 11‐year retrospective cohort study. BMC Infect Dis 13: 48 source

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  • Premisecitation

    Polymorphisms in host genes encoding iron-binding proteins that counter microbial siderophores or other iron uptake systems enhance resistance to bacterial infections.

    “Along this line, polymorphisms in host genes encoding Fe-binding proteins that counter microbial siderophores or other microbial Fe uptake systems enhance resistance to bacterial infections [34].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Barber MF, Elde NC (2014) Nutritional immunity. Escape from bacterial iron piracy through rapid evolution of transferrin. Science 346: 1362–1366 source

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  • Premisecitation

    ROS and RNS have high affinity toward Fe2+ in prosthetic heme groups or Fe-sulfur clusters of various proteins, including IRPs, whose stability and activity they modulate.

    “Both ROS and RNS have high affinity toward Fe 2+ in the prosthetic heme groups or Fe-sulfur clusters of a variety of proteins [79,80].These include IRPs, to which NO can bind and modulate their stability as well as activity [81,82], resulting in IRE-mediated regulation of Fe metabolism [58,66,[81][82][83][84][85][86].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [79] Nathan CF, Hibbs JB Jr (1991) Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr Opin Immunol 3: 65–70 source

      Not checked in the free run.

    • cites [80] Bogdan C (2001) Nitric oxide and the immune response. Nat Immunol 2: 907–916 source

      Not checked in the free run.

    • cites [81] Weiss G, Goossen B, Doppler W, Fuchs D, Pantopoulos K, Werner‐Felmayer G, Wachter H, Hentze MW (1993) Translational regulation via iron‐responsive elements by the nitric oxide/NO‐synthase pathway. EMBO J 12: 3651–3657 source

      Not checked in the free run.

    • cites [82] Drapier JC, Hirling H, Wietzerbin J, Kaldy P, Kuhn LC (1993) Biosynthesis of nitric oxide activates iron regulatory factor in macrophages. EMBO J 12: 3643–3649 source

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  • May combine two claims. 70
  • Classified as probably not a substantial claim. 18
  • The quote only partly states this claim. 1

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    Findingown data

    Heme-driven programmed cell death is suppressed by RIPK1 inhibition and Ripk3 deletion.

    “However, heme-driven programmed cell death is also suppressed by pharmacologic inhibition of the receptor-interacting serine/threonine kinases 1 (RIPK1), as well as by the deletion of the Ripk3 gene (unpublished observation).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Mice with Fth deletion develop tissue Fe overload and tissue damage and succumb to Plasmodium and polymicrobial infections.

    “Mice in which the Fth allele is deleted develop tissue Fe overload and tissue damage succumbing to Plasmodium [107] as well as to polymicrobial infections (unpublished observation).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [107] Gozzelino R, Andrade BB, Larsen R, Luz NF, Vanoaica L, Seixas E, Coutinho A, Cardoso S, Rebelo S, Poli M et al (2012) Metabolic adaptation to tissue iron overload confers tolerance to malaria. Cell Host Microbe 12: 693–704 source

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

    Premisecitation

    Disease tolerance limits the impact of infection on host integrity and fitness without interfering with pathogen burden, and is distinct from immunological tolerance.

    “It limits the impact of infection on host integrity and fitness without interfering with the host's pathogen burden [14].This is distinct from immunological tolerance [15], and while the two may be functionally linked, they act via distinct mechanisms.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Caldwell RM, Schafer JF, Compton LE, Patterson FL (1958) Tolerance to cereal leaf rusts. Science 128: 714–715 source

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    • cites [15] Medawar PB (1961) Immunological tolerance. Nature 189: 14–17 source

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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Host defense strategies that limit microbial pathogenicity comprise resistance mechanisms, which negatively impact microbes, and disease tolerance mechanisms, which sustain host homeostasis without directly interfering with microbes.

    “Host defense strategies that limit microbial pathogenicity include resistance mechanisms that exert a negative impact on microbes, and disease tolerance mechanisms that sustain host homeostasis without interfering directly with microbes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Some resistance mechanisms, including those involved in nutritional immunity, can compromise host homeostasis, and this trade-off is countered by tissue damage control, which confers disease tolerance to infection.

    “While essential to confer host protection against infection, some resistance mechanisms, including those involved in nutritional immunity, can compromise host homeostasis [10].This trade-off is countered by an additional host defense strategy termed as tissue damage control [1,11], which confers disease tolerance to infection [1,12,13].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [10] Kotas ME, Medzhitov R (2015) Homeostasis, inflammation, and disease susceptibility. Cell 160: 816–827 source

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    • cites [1] Medzhitov R, Schneider DS, Soares MP (2012) Disease tolerance as a defense strategy. Science 335: 936–941 source

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    • cites [11] Soares MP, Gozzelino R, Weis S (2014) Tissue damage control in disease tolerance. Trends Immunol 35: 483–494 source

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    • cites [12] Ayres JS, Schneider DS (2012) Tolerance of infections. Annu Rev Immunol 30: 271–294 source

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    • cites [13] Schneider DS, Ayres JS (2008) Two ways to survive infection: what resistance and tolerance can teach us about treating infectious diseases. Nat Rev Immunol 8: 889–895 source

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  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Pathogen class-specific mechanisms regulating iron metabolism evolved to confer protection against intracellular versus extracellular pathogens.

    “We will put forward the notion that pathogen class-specific mechanisms regulating Fe metabolism evolved to confer protection against intracellular versus extracellular pathogens.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Nutritional immunity, a defense strategy encompassing restriction of microbial access to iron and other trace metals such as zinc, manganese, and copper, is a central defense strategy against infection.

    “This defense strategy, termed nutritional immunity [4], encompasses mechanisms that restrict microbes from accessing iron (Fe) [5][6][7] as well as other trace metals such as zinc, manganese, or copper [8,9].”
    • Also stated in: § Introduction · boosted
      “That nutritional immunity is a central defense strategy against infection is supported by the realization that several "infection resistance genes" act via a mechanism controlling host Fe metabolism.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [4] Weinberg ED (1975) Nutritional immunity. Host's attempt to withold iron from microbial invaders. JAMA 231: 39–41 source

      Not checked in the free run.

    • cites [5] Weinberg ED (2009) Iron availability and infection. Biochim Biophys Acta 1790: 600–605 source

      Not checked in the free run.

    • cites [6] Nairz M, Haschka D, Demetz E, Weiss G (2014) Iron at the interface of immunity and infection. Front Pharmacol 5: 152 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Adaptive responses that supply iron to microbes generally increase their pathogenicity, while those that withhold iron from microbes limit their virulence.

    “The general principle being that adaptive responses supplying Fe to microbes increase, in most cases, their pathogenicity while those withholding Fe from microbes limit their virulence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Regulation of macrophage intracellular iron content by the hepcidin/FPN axis impacts macrophage polarization and presumably resistance to infection.

    “Regulation of Mø intracellular Fe content by the hepcidin/FPN axis impacts on Mø polarization and presumably therefore resistance to infection [6,66,67].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] Nairz M, Haschka D, Demetz E, Weiss G (2014) Iron at the interface of immunity and infection. Front Pharmacol 5: 152 source

      Not checked in the free run.

    • cites [66] Recalcati S, Locati M, Marini A, Santambrogio P, Zaninotto F, De Pizzol M, Zammataro L, Girelli D, Cairo G (2010) Differential regulation of iron homeostasis during human macrophage polarized activation. Eur J Immunol 40: 824–835 source

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    Premisecitation

    Polymorphisms in the human HMOX1 gene coding for HO-1 are associated with HIV infection and malaria.

    “This also holds true for polymorphisms in the human HMOX1 gene coding for HO-1, as illustrated for HIV infection [44] and malaria [45,46].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [44] Seu L, Burt TD, Witte JS, Martin JN, Deeks SG, McCune JM (2012) Variations in the heme oxygenase‐1 microsatellite polymorphism are associated with plasma CD14 and viral load in HIV‐infected African‐Americans. Genes Immun 13: 258–267 source

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    • cites [45] Walther M, De Caul A, Aka P, Njie M, Amambua‐Ngwa A, Walther B, Predazzi IM, Cunnington A, Deininger S, Takem EN et al (2012) HMOX1 gene promoter alleles and high HO‐1 levels are associated with severe malaria in Gambian children. PLoS Pathog 8: e1002579 source

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    • cites [46] Sambo MR, Trovoada MJ, Benchimol C, Quinhentos V, Gonçalves L, Velosa R, Marques MI, Sepúlveda N, Clark TG, Mustafa S et al (2010) Transforming growth factor beta 2 and heme oxygenase 1 genes are risk factors for the cerebral malaria syndrome in angolan children. PLoS ONE 5: e11141 source

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

    Premisecitation

    More than 80% of bioavailable iron in mammals exists as heme contained in hemoproteins.

    “More than 80% of the bioavailable Fe in mammals exists in the form of heme contained in hemoproteins [241].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [241] Fischer H, Zeile K (1929) Synthese des haematoporphyrins, protoporphyrins und haemins. Justus Liebigs Annalen der Chemie 468: 98–116 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hepcidin expression is repressed by hypoferremia, anemia, tissue hypoxia, and hormones such as GDF15, erythroferrone, PDGF-BB, and testosterone.

    “and repressed in response to: (i) hypoferremia, that is, lower than normal levels of circulating Fe, (ii) anemia, (iii) tissue hypoxia, and (iv) hormones, for example, growth and differentiation factors 15, erythroferrone, platelet-derived growth factor-BB (PDGF-BB) and testosterone [62][63][64][65].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [62] Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T (2014) Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet 46: 678–684 source

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  • May combine two claims.

    Premisecitation

    Accumulation of intracellular iron in T cells mitigates the activation, differentiation, and proliferation of TH1 cells while fostering TH2 responses, as illustrated in Candida albicans infection in mice.

    “Moreover, accumulation of intracellular Fe in T cells mitigates the activation, differentiation, and proliferation of T H 1 cells while fostering T H type 2 (T H 2) responses, as illustrated in the context of Candida albicans infection in mice [69,71].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisecitation

    NOX2/gp91phox and iNOS/NOS2 are prototypical hemoproteins that use Fe-heme to catalyze the production of reactive oxygen species and reactive nitrogen species, respectively.

    “Both NOX2/gp91 phox and iNOS/ NOS2 are prototypical hemoproteins that use Fe-heme to catalyze the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), respectively [76].”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Hepcidin-independent hypoferremia occurs in mouse models of inflammation, and TNF causes sustained hypoferremia in mice irrespective of hepcidin.

    “The physiologic relevance of this mechanism was recently underpinned by the description of hepcidin-independent hypoferremia in mouse models of inflammation [87], and the fact that tumor necrosis factor (TNF) causes sustained hypoferremia in mice, irrespective of hepcidin [88].”
    Quote in the paperSubstantial claim0 of 2 sources checked
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  • May combine two claims.

    Premisecitation

    Hepcidin expression is induced by hyperferremia, cytokines such as IL-1, IL-6, and IL-22, and recognition of bacterial lipopolysaccharide by TLR4.

    “Hepcidin expression is regulated mainly at the level of transcription of the hepcidin (HAMP) gene, being induced in response to: (i) hyperferremia, that is, higher than normal levels of circulating Fe, (ii) cytokines, for example, interleukin (IL)-1, IL-6, and IL-22, or (iii) recognition of bacterial lipopolysaccharide by Toll-like receptor 4 (TLR4) [59][60][61]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
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    Premisecitation

    IFNγ induces iNOS/NOS2 expression via STAT transcription factors, and NO produced by iNOS/NOS2 regulates IRP binding affinities toward IRE in TfR and ferritin, inhibiting cellular iron import and intracellular retention.

    “IFNc also induces the expression of iNOS/NOS2 [78], via a mechanism regulated at a transcriptional level by the activation of the signal transducers and activators of transcription (STAT) family of transcription factors (Fig 2).As described above, the NO produced by iNOS/NOS2 regulates the binding affinities of IRP toward target IRE in genes such as transferrin receptor (TfR) and ferritin, inhibit”
    Quote in the paperSubstantial claim0 of 5 sources checked
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    • cites [81] Weiss G, Goossen B, Doppler W, Fuchs D, Pantopoulos K, Werner‐Felmayer G, Wachter H, Hentze MW (1993) Translational regulation via iron‐responsive elements by the nitric oxide/NO‐synthase pathway. EMBO J 12: 3651–3657 source

      Not checked in the free run.

    • cites [82] Drapier JC, Hirling H, Wietzerbin J, Kaldy P, Kuhn LC (1993) Biosynthesis of nitric oxide activates iron regulatory factor in macrophages. EMBO J 12: 3643–3649 source

      Not checked in the free run.

    • cites [111] Pantopoulos K, Weiss G, Hentze MW (1996) Nitric oxide and oxidative stress (H2O2) control mammalian iron metabolism by different pathways. Mol Cell Biol 16: 3781–3788 source

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    Premisecitation

    IL-10 and IL-6 increase heme uptake from hemoglobin-haptoglobin or heme-HPX complexes via induction of CD163 and CD91, coupled to HO-1 induction in macrophages.

    “Moreover, IL-10 and IL-6 also increase heme uptake from circulating hemoglobin-haptoglobin or heme-HPX complexes, via a mechanism involving the induction of the hemoglobin scavenger receptor CD163 and the HPX scavenger receptor CD91 [114,115], respectively (Fig 2).This is coupled to the induction of HO-1 in Mø [116], which extracts Fe from heme and promotes intracellular Fe storage by ferritin (”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [114] Hvidberg V, Maniecki MB, Jacobsen C, Hojrup P, Moller HJ, Moestrup SK (2005) Identification of the receptor scavenging hemopexin‐heme complexes. Blood 106: 2572–2579 source

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    • cites [116] Lee TS, Chau LY (2002) Heme oxygenase‐1 mediates the anti‐inflammatory effect of interleukin‐10 in mice. Nat Med 8: 240–246 source

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    Premisecitation

    Activated macrophages express and release lactoferrin, which scavenges and restricts iron availability to extracellular pathogens, protects macrophages from oxidative stress, and modulates their microbicidal activity.

    “Activated Mø express and release lactoferrin, which scavenges and restricts Fe availability to extracellular pathogens [6,117,118] (Fig 2).Lactoferrin also protects Mø from oxidative stress [117,119] and modulates Mø microbicidal activity, as shown in the context of Staphylococcus aureus infection [120,121].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [6] Nairz M, Haschka D, Demetz E, Weiss G (2014) Iron at the interface of immunity and infection. Front Pharmacol 5: 152 source

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    • cites [117] Brock JH (2002) The physiology of lactoferrin. Biochem Cell Biol 80: 1–6 source

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    • cites [118] Kontoghiorghes GJ, Weinberg ED (1995) Iron: mammalian defense systems, mechanisms of disease, and chelation therapy approaches. Blood Rev 9: 33–45 source

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    • cites [119] Fischer R, Debbabi H, Dubarry M, Boyaka P, Tome D (2006) Regulation of physiological and pathological Th1 and Th2 responses by lactoferrin. Biochem Cell Biol 84: 303–311 source

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    • cites [120] Hwang SA, Kruzel ML, Actor JK (2014) Immunomodulatory effects of recombinant lactoferrin during MRSA infection. Int Immunopharmacol 20: 157–163 source

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  • May combine two claims.

    Premisecitation

    Heme catabolism and subsequent intracellular iron storage by ferritin confers host protection against the blood stage of Plasmodium infection while increasing susceptibility to intracellular Salmonella.

    “For example, heme catabolism by and subsequent intracellular Fe storage by ferritin [54,107] confers host protection against the blood stage of Plasmodium infection while increasing susceptibility to the intracellular bacteria Salmonella [108].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [54] Gozzelino R, Soares MP (2014) Coupling heme and iron metabolism via ferritin H chain. Antioxid Redox Signal 20: 1754–1769 source

      Not checked in the free run.

    • cites [107] Gozzelino R, Andrade BB, Larsen R, Luz NF, Vanoaica L, Seixas E, Coutinho A, Cardoso S, Rebelo S, Poli M et al (2012) Metabolic adaptation to tissue iron overload confers tolerance to malaria. Cell Host Microbe 12: 693–704 source

      Not checked in the free run.

    • cites [108] Cunnington AJ, de Souza JB, Walther M, Riley EM (2012) Malaria impairs resistance to Salmonella through heme‐ and heme oxygenase‐dependent dysfunctional granulocyte mobilization. Nat Med 18: 120–127 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The general strategy to restrict iron access to extracellular pathogens consists in retention of intracellular iron by macrophages leading to hypoferremia, achieved by inducing iron import and retention and suppressing cellular iron export.

    “The general strategy to restrict Fe access to extracellular pathogens consists in the retention of intracellular Fe by Mø leading to hypoferremia (Fig 2).This is achieved essentially by the induction of Fe import and retention mechanisms, coupled to suppression of cellular Fe export (Fig 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Lipocalin (Lcn2/NGAL) is produced by activated PMN cells and macrophages and captures iron-laden bacterial catecholate siderophores such as enterobactin, inhibiting bacterial acquisition of siderophore-bound iron.

    “Lipocalin (Lcn2/NGAL) is a peptide produced by activated polymorphonuclear (PMN) cells and Mø, which captures Fe-laden bacterial catechole type siderophores, such as enterobactin, derived from Gram-negative bacteria (Fig 2).Lcn2 inhibits the acquisition of siderophore-bound Fe by bacteria, as illustrated for E. coli or Klebsiella spp.[129,130].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [129] Flo TH, Smith KD, Sato S, Rodriguez DJ, Holmes MA, Strong RK, Akira S, Aderem A (2004) Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432: 917–921 source

      Not checked in the free run.

    • cites [130] Berger T, Togawa A, Duncan GS, Elia AJ, You‐Ten A, Wakeham A, Fong HE, Cheung CC, Mak TW (2006) Lipocalin 2‐deficient mice exhibit increased sensitivity to Escherichia coli infection but not to ischemia‐reperfusion injury. Proc Natl Acad Sci USA 103: 1834–1839 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lactoferrin, a transferrin-family iron-binding protein expressed in many tissues and secretions, binds and restricts iron delivery to extracellular microbes, accounting for its antimicrobial activity in breast milk.

    “Lactoferrin is expressed in many tissues and secretions where its primary function is to bind and restrict Fe delivery to extracellular microbes, a mechanism which accounts for its antimicrobial activity in breast milk [117].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Brock JH (2002) The physiology of lactoferrin. Biochem Cell Biol 80: 1–6 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Once intracellular iron levels increase in macrophages, iNOS/NOS2 transcription is repressed, creating a negative feedback loop that promotes intracellular iron retention.

    “However, once intracellular Fe levels increase in Mø, iNOS/NOS2 transcription is repressed creating a negative feedback loop, which promotes intracellular Fe retention [85,111].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [85] Weiss G, Wachter H, Fuchs D (1995) Linkage of cell‐mediated immunity to iron metabolism. Immunol Today 16: 495–500 source

      Not checked in the free run.

    • cites [111] Pantopoulos K, Weiss G, Hentze MW (1996) Nitric oxide and oxidative stress (H2O2) control mammalian iron metabolism by different pathways. Mol Cell Biol 16: 3781–3788 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lcn2 delivers bacterial and mammalian siderophore-bound iron to the Lcn2 receptor on host cells, suggesting it modulates iron trafficking during infection.

    “Lcn2 delivers bacterial as well as mammalian siderophore-bound Fe [131,132] to the Lcn2 receptor expressed by host cells, suggesting that it modulates Fe trafficking and hence Fe metabolism during infection (Fig 2).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [131] Devireddy LR, Hart DO, Goetz DH, Green MR (2010) A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production. Cell 141: 1006–1017 source

      Not checked in the free run.

    • cites [132] Bao G, Clifton M, Hoette TM, Mori K, Deng SX, Qiu A, Viltard M, Williams D, Paragas N, Leete T et al (2010) Iron traffics in circulation bound to a siderocalin (Ngal)‐catechol complex. Nat Chem Biol 6: 602–609 source

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  • May combine two claims.

    Premisecitation

    Murine macrophages lacking functional Nramp1 have higher intracellular iron content, whereas functional Nramp1 decreases intracellular iron content, conferring protection against intracellular infections, an effect traced to modulation of FPN expression.

    “Murine Mø lacking functional Nramp1 have a higher intracellular Fe content, whereas functional Nramp1 decreases intracellular Fe content, conferring protection against intracellular infections [145,148,149], an effect traced back to modulation of FPN expression [150].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [145] Cellier MF (2012) Nutritional immunity: homology modeling of Nramp metal import. Adv Exp Med Biol 946: 335–351 source

      Not checked in the free run.

    • cites [148] Barton CH, Biggs TE, Baker ST, Bowen H, Atkinson PG (1999) Nramp1: a link between intracellular iron transport and innate resistance to intracellular pathogens. J Leukoc Biol 66: 757–762 source

      Not checked in the free run.

    • cites [149] Fritsche G, Nairz M, Theurl I, Mair S, Bellmann‐Weiler R, Barton HC, Weiss G (2007) Modulation of macrophage iron transport by Nramp1 (Slc11a1). Immunobiology 212: 751–757 source

      Not checked in the free run.

    • cites [150] Nairz M, Fritsche G, Crouch ML, Barton HC, Fang FC, Weiss G (2009) Slc11a1 limits intracellular growth of Salmonella enterica sv. Typhimurium by promoting macrophage immune effector functions and impairing bacterial iron acquisition. Cell Microbiol 11: 1365–1381 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NRAMP1 increases production of NO and TNF in infected macrophages while reducing IL-10 secretion, indicating that modulation of intracellular iron content regulates macrophage antimicrobial effector function.

    “NRAMP1 increases the production of NO and TNF in infected Mø, whereas IL-10 secretion is reduced, arguing again that modulation of intracellular Fe content regulates Mø antimicrobial effector function [152-155].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [152] Fritsche G, Dlaska M, Barton H, Theurl I, Garimorth K, Weiss G (2003) Nramp1 functionality increases inducible nitric oxide synthase transcription via stimulation of IFN regulatory factor 1 expression. J Immunol 171: 1994–1998 source

      Not checked in the free run.

    • cites [153] Fritsche G, Nairz M, Werner ER, Barton HC, Weiss G (2008) Nramp1‐functionality increases iNOS expression via repression of IL‐10 formation. Eur J Immunol 38: 3060–3067 source

      Not checked in the free run.

    • cites [154] Barton CH, Whitehead SH, Blackwell JM (1995) Nramp transfection transfers Ity/Lsh/Bcg‐related pleiotropic effects on macrophage activation: influence on oxidative burst and nitric oxide pathways. Mol Med 1: 267–279 source

      Not checked in the free run.

    • cites [155] Mulero V, Searle S, Blackwell JM, Brock JH (2002) Solute carrier 11a1 (Slc11a1; formerly Nramp1) regulates metabolism and release of iron acquired by phagocytic, but not transferrin‐receptor‐mediated, iron uptake. Biochem J 363: 89–94 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Extracellular hemoglobin acts both as a soluble pattern recognition receptor and as a cytotoxic effector molecule targeting extracellular pathogens.

    “Overall, this suggests that extracellular hemoglobin acts both as a soluble pattern recognition receptors (PRRs) and as a cytotoxic effector molecule targeting extracellular pathogens [140].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] Lee SK, Ding JL (2013) A perspective on the role of extracellular hemoglobin on the innate immune system. DNA Cell Biol 32: 36–40 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Extracellular hemoglobin exerts antimicrobial effects driven by peroxidase activity of iron in its prosthetic heme groups, and binding to bacterial LPS elicits conformational changes enhancing its peroxidase and microbicidal activity.

    “Extracellular hemoglobin exerts antimicrobial effects, driven by the peroxidase activity of the Fe contained in its prosthetic heme groups [138,139].Furthermore, binding of extracellular hemoglobin to bacterial LPS [140] elicits conformational changes in the tertiary structure of hemoglobin [139,141], which enhance its peroxidase and microbicidal activity [138,139].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [138] Jiang N, Tan NS, Ho B, Ding JL (2007) Respiratory protein‐generated reactive oxygen species as an antimicrobial strategy. Nat Immunol 8: 1114–1122 source

      Not checked in the free run.

    • cites [139] Du R, Ho B, Ding JL (2010) Rapid reprogramming of haemoglobin structure‐function exposes multiple dual‐antimicrobial potencies. EMBO J 29: 632–642 source

      Not checked in the free run.

    • cites [140] Lee SK, Ding JL (2013) A perspective on the role of extracellular hemoglobin on the innate immune system. DNA Cell Biol 32: 36–40 source

      Not checked in the free run.

    • cites [141] Kaca W, Roth RI, Levin J (1994) Hemoglobin, a newly recognized lipopolysaccharide (LPS)‐binding protein that enhances LPS biological activity. J Biol Chem 269: 25078–25084 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NRAMP1 confers resistance to intracellular bacteria such as Salmonella via induction of Lcn2 expression, and Lcn2 can control proliferation of intracellular bacteria that do not produce siderophores, such as Chlamydia pneumoniae.

    “There is at least one additional mechanism by which NRAMP1 confers resistance to intracellular bacteria such as Salmonella, namely via the induction of Lcn2 expression [156].Of note, Lcn2 can control the proliferation of intracellular bacteria that do not produce siderophores, such as Chlamydia pneumonia [157] (Fig 3).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [156] Fritsche G, Nairz M, Libby SJ, Fang FC, Weiss G (2012) Slc11a1 (Nramp1) impairs growth of Salmonella enterica serovar typhimurium in macrophages via stimulation of lipocalin‐2 expression. J Leukoc Biol 92: 353–359 source

      Not checked in the free run.

    • cites [157] Bellmann‐Weiler R, Schroll A, Engl S, Nairz M, Talasz H, Seifert M, Weiss G (2013) Neutrophil gelatinase‐associated lipocalin and interleukin‐10 regulate intramacrophage Chlamydia pneumoniae replication by modulating intracellular iron homeostasis. Immunobiology 218: 969–978 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lcn2 exerts contrasting effects depending on pathogen and tissue localization, improving or mitigating resistance; it aggravates Streptococcus pneumoniae infection through an immunomodulatory effect possibly via iron metabolism regulation.

    “It should be noted, however, that Lcn2 exerts contrasting effects depending on the pathogen and tissue localization, improving or mitigating resistance to infection.For example, Lcn2 aggravates the outcome of Streptococcus pneumoniae infection [134] through a immunomodulatory effect possibly acting via regulation of Fe metabolism or another not yet fully elucidated pathway [135,136].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [134] Warszawska JM, Gawish R, Sharif O, Sigel S, Doninger B, Lakovits K, Mesteri I, Nairz M, Boon L, Spiel A et al (2013) Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes. J Clin Invest 123: 3363–3372 source

      Not checked in the free run.

    • cites [135] Chakraborty S, Kaur S, Guha S, Batra SK (2012) The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer. Biochim Biophys Acta 1826: 129–169

      Not checked in the free run.

    • cites [136] Liu Z, Petersen R, Devireddy L (2013) Impaired neutrophil function in 24p3 null mice contributes to enhanced susceptibility to bacterial infections. J Immunol 190: 4692–4706 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Individuals carrying mutations in the FPN gene, associated with intracellular iron retention and secondary siderosis in Africa (Bantu disease), have increased incidence of Mycobacteria infection and higher mortality from tuberculosis.

    “The pathophysiologic relevance of this mechanism is illustrated by the fact that individuals carrying mutations in the FPN gene, which is associated with intracellular Fe retention and secondary siderosis in Africa (also termed Bantu disease), are challenged with an increased incidence of Mycobacteria infection and higher mortality from tuberculosis [162].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [162] Gordeuk VR, Caleffi A, Corradini E, Ferrara F, Jones RA, Castro O, Onyekwere O, Kittles R, Pignatti E, Montosi G et al (2003) Iron overload in Africans and African‐Americans and a common mutation in the SCL40A1 (ferroportin 1) gene small star, filled. Blood Cells Mol Dis 31: 299–304 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Several mechanisms evolved to regulate host iron metabolism in a manner that limits the proliferation capacity and virulence of extracellular pathogens, and leakage of hemoglobin from red blood cells appears to be an ancestral, evolutionarily conserved defense strategy targeting extracellular pathogens for heme-driven oxidative cytotoxicity.

    “Taken together, these observations argue that several mechanisms evolved to regulate host Fe metabolism in a manner that limits the proliferation capacity and virulence of extracellular pathogens.Moreover, leakage of hemoglobin from red blood cells appears to be an ancestral and evolutionary conserved defense strategy that targets extracellular pathogens for heme-driven oxidative cytotoxicity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    NRAMP1 is a transmembrane transporter in late phagosomes that regulates phagosome acidification and pH-dependent shuttling of divalent metals including iron, zinc, and manganese across the phagolysosomal membrane.

    “NRAMP1 is a transmembrane transporter expressed in late phagosomes, where it exerts multiple functions including regulation of phagosome acidification, which is, however, exerted mainly by v-ATPase [144] along with pH-dependent shuttling of divalent metals, including Fe, zinc and manganese, across the phagolysosomal membrane [145-147] (Fig 3).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [144] Sturgill‐Koszycki S, Schlesinger PH, Chakraborty P, Haddix PL, Collins HL, Fok AK, Allen RD, Gluck SL, Heuser J, Russell DG et al (1994) Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton‐ATPase. Science 263: 678–681 source

      Not checked in the free run.

    • cites [145] Cellier MF (2012) Nutritional immunity: homology modeling of Nramp metal import. Adv Exp Med Biol 946: 335–351 source

      Not checked in the free run.

    • cites [146] Hackam DJ, Rotstein OD, Zhang W, Gruenheid S, Gros P, Grinstein S (1998) Host resistance to intracellular infection: mutation of natural resistance‐associated macrophage protein 1 (Nramp1) impairs phagosomal acidification. J Exp Med 188: 351–364 source

      Not checked in the free run.

    • cites [147] Jabado N, Jankowski A, Dougaparsad S, Picard V, Grinstein S, Gros P (2000) Natural resistance to intracellular infections: natural resistance‐associated macrophage protein 1 (Nramp1) functions as a pH‐dependent manganese transporter at the phagosomal membrane. J Exp Med 192: 1237–1248 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    E. coli can use the mammalian siderophore 2,5-DHBA as an iron source, and macrophages respond to bacterial challenge by downregulating 2,5-DHBA synthesis, leading to its depletion and enhanced resistance to E. coli infection.

    “Of note, E. coli can use the mammalian siderophore, 2,5-dihydroxy-benzoic acid (2,5-DHBA) as Fe source [137].Accordingly, Mø respond to bacterial challenge by downregulating 2,5-DHBA synthesis, leading to 2,5-DHBA depletion and enhanced resistance to E. coli infection.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [137] Liu Z, Reba S, Chen WD, Porwal SK, Boom WH, Petersen RB, Rojas R, Viswanathan R, Devireddy L (2014) Regulation of mammalian siderophore 2,5‐DHBA in the innate immune response to infection. J Exp Med 211: 1197–1213 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NO produced by iNOS/NOS2 in activated macrophages activates Nrf2 and induces FPN expression, reducing macrophage intracellular iron content and conferring resistance to Salmonella infection; impaired resistance in iNos/Nos2-deficient mice can be restored by pharmacologic iron chelation.

    “Namely, when produced by iNOS/NOS2 in activated Mø, NO activates Nrf2 and induces the transcription/expression of FPN, which reduces Mø intracellular Fe content and confers resistance to Salmonella infection [73] (Fig 3).Of note, impaired resistance to Salmonella infection in iNos/Nos2-deficient mice can be restored by pharmacologic Fe chelation, arguing that the microbicidal effect of NO acts, at”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Nairz M, Schleicher U, Schroll A, Sonnweber T, Theurl I, Ludwiczek S, Talasz H, Brandacher G, Moser PL, Muckenthaler MU et al (2013) Nitric oxide‐mediated regulation of ferroportin‐1 controls macrophage iron homeostasis and immune function in Salmonella infection. J Exp Med 210: 855–873 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Immune-driven resistance mechanisms can cause systemic reduction of circulating iron (hypoferremia), compensated by expansion of iron stores in the reticuloendothelial system (hyperferritinemia).

    “As discussed above, some immune-driven resistance mechanisms can encompass subtle alterations of host Fe metabolism characterized by a systemic”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Intracellular iron accumulation in macrophages represses IFNγ receptor signaling, most likely explaining why reducing intracellular iron content promotes IFNγ-driven resistance pathways involving MHC class II, iNOS/NOS2, TNF, IL-6, or IL-12 expression.

    “Intracellular Fe accumulation in Mø represses IFNc receptor signaling, most likely explaining why reducing intracellular Fe content promotes IFNc-driven resistance pathways involving the induction of histocompatibility (MHC) class II, iNOS/NOS2 TNF, IL-6, or IL-12 expression [164][165][166][167].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [164] Oexle H, Kaser A, Most J, Bellmann‐Weiler R, Werner ER, Werner‐Felmayer G, Weiss G (2003) Pathways for the regulation of interferon‐gamma‐inducible genes by iron in human monocytic cells. J Leukoc Biol 74: 287–294 source

      Not checked in the free run.

    • cites [165] Melillo G, Taylor LS, Brooks A, Musso T, Cox GW, Varesio L (1997) Functional requirement of the hypoxia‐responsive element in the activation of the inducible nitric oxide synthase promoter by the iron chelator desferrioxamine. J Biol Chem 272: 12236–12243 source

      Not checked in the free run.

    • cites [166] Dlaska M, Weiss G (1999) Central role of transcription factor NF‐IL6 for cytokine and iron‐mediated regulation of murine inducible nitric oxide synthase expression. J Immunol 162: 6171–6177 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IRP expression and its regulatory effects on cellular iron homeostasis in macrophages confer resistance to Salmonella infection by restricting iron availability to the bacterium and promoting antimicrobial immune effector mechanisms.

    “This is in line with the recent observation that IRP expression and their subsequent regulatory effects on cellular Fe homeostasis in Mø confer resistance to Salmonella infection by restricting Fe availability to the bacterium and by promoting antimicrobial immune effector mechanisms of Mø [168].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [168] Nairz M, Ferring‐Appel D, Casarrubea D, Sonnweber T, Viatte L, Schroll A, Haschka D, Fang FC, Hentze MW, Weiss G, Galy B (2015) Iron regulatory proteins mediate host resistance to Salmonella. Cell Host Microbe 18: 254–261 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Salmonella promotes hepcidin expression in the liver via induction of an estrogen receptor gamma-mediated cascade, and subsequent FPN degradation favors intracellular iron accumulation, promoting pathogen growth.

    “Of interest, some intracellular bacteria can counterbalance this host response, as illustrated for Salmonella spp., which promotes the expression of hepcidin in the liver via the induction of estrogen receptor gamma-mediated cascade.Subsequent degradation of FPN favors intracellular Fe accumulation, thereby promoting pathogen growth [163].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [163] Kim DK, Jeong JH, Lee JM, Kim KS, Park SH, Kim YD, Koh M, Shin M, Jung YS, Kim H et al (2014) Inverse agonist of estrogen‐related receptor gamma controls Salmonella typhimurium infection by modulating host iron homeostasis. Nat Med 20: 419–424 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ferrylhemoglobin aggregates deposited on vascular endothelial cells become vasoactive and pro-inflammatory.

    “When deposited on the surface of vascular endothelial cells, these become vasoactive and pro-inflammatory [198], presumably contributing to the pathogenesis of systemic infections associated with hemolysis and vasculitis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [198] Silva G, Jeney V, Chora A, Larsen R, Balla J, Soares MP (2009) Oxidized hemoglobin is an endogenous proinflammatory agonist that targets vascular endothelial cells. J Biol Chem 284: 29582–29595 source

      Not checked in the free run.

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

    Interpretationcitation

    NO scavenging by extracellular hemoglobin impairs disease tolerance to Plasmodium infection in mice.

    “This was suggested to contribute to the pathogenesis of severe forms of malaria in mice, without interfering with host pathogen burden [192], thus arguing that NO scavenging by extracellular hemoglobin impairs disease tolerance to Plasmodium infection.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [192] Gramaglia I, Sobolewski P, Meays D, Contreras R, Nolan JP, Frangos JA, Intaglietta M, van der Heyde HC (2006) Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria. Nat Med 12: 1417–1422 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The cytoprotective effect of CO likely prevents infected macrophages from undergoing necroptosis, supporting granuloma formation and resistance to Mycobacteria.

    “While it is not clear whether this effect is mediated via CO and/or other products of heme catabolism, such as biliverdin and Fe, it is likely that the cytoprotective effect of CO [172] prevents infected Mø from undergoing programmed cell death by necroptosis [173].This cytoprotective effect should support granuloma formation and hence resistance to Mycobacteria [170,171].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [172] Brouard S, Otterbein LE, Anrather J, Tobiasch E, Bach FH, Choi AM, Soares MP (2000) Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. J Exp Med 192: 1015–1026 source

      Not checked in the free run.

    • cites [173] Fortes GB, Alves LS, de Oliveira R, Dutra FF, Rodrigues D, Fernandez PL, Souto‐Padron T, De Rosa MJ, Kelliher M, Golenbock D et al (2012) Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production. Blood 119: 2368–2375 source

      Not checked in the free run.

    • cites [170] Silva‐Gomes S, Appelberg R, Larsen R, Soares MP, Gomes MS (2013) Heme catabolism by heme oxygenase‐1 confers host resistance to Mycobacterium infection. Infect Immun 81: 2536–2545 source

      Not checked in the free run.

    • cites [171] Regev D, Surolia R, Karki S, Zolak J, Montes‐Worboys A, Oliva O, Guroji P, Saini V, Steyn AJ, Agarwal A et al (2012) Heme oxygenase‐1 promotes granuloma development and protects against dissemination of mycobacteria. Lab Invest 92: 1541–1552 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Extracellular hemoglobin impairs disease tolerance to sepsis and malaria, as these pathologic conditions can be dissociated from host pathogen burden.

    “These often-lethal pathologic conditions can be dissociated from host pathogen burden, suggesting that extracellular hemoglobin impairs disease tolerance to sepsis and malaria.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    IFNγ receptor signaling induces FPN expression while inhibiting transferrin receptor-mediated iron uptake and inducing Lcn2 expression in macrophages.

    “Finally, signaling via the IFNc receptor also induces FPN expression while inhibiting extracellular Fe uptake via the transferrin receptor [169] and inducing Lcn2 expression [135] in Mø (Fig 3).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [169] Nairz M, Fritsche G, Brunner P, Talasz H, Hantke K, Weiss G (2008) Interferon‐gamma limits the availability of iron for intramacrophage Salmonella typhimurium. Eur J Immunol 38: 1923–1936 source

      Not checked in the free run.

    • cites [135] Chakraborty S, Kaur S, Guha S, Batra SK (2012) The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer. Biochim Biophys Acta 1826: 129–169

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Macrophage necroptosis impairs granuloma formation and compromises resistance to Mycobacteria infection in zebrafish.

    “The recent finding that Mø necroptosis impairs granuloma formation and compromises resistance to Mycobacteria infection in zebrafish supports this notion [174].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [174] Roca FJ, Ramakrishnan L (2013) TNF dually mediates resistance and susceptibility to mycobacteria via mitochondrial reactive oxygen species. Cell 153: 521–534 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Several mechanisms evolved to reduce the intracellular iron content of macrophages infected by intracellular pathogens, limiting iron access to pathogens while modulating macrophage polarization and maintaining viability, thereby limiting virulence and clearing pathogens.

    “It appears that several mechanisms evolved to reduce the intracellular Fe content of Mø infected by intracellular pathogens.This achieves several goals, namely to limit Fe access to intracellular pathogens while modulating Mø polarization and maintaining Mø viability, all of which concur to limit the virulence and eventually clear intracellular pathogens.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Mechanisms reducing intracellular iron availability in macrophages have a dual role: limiting microbial access to intracellular iron while boosting antimicrobial resistance mechanisms in response to cytokines such as IFNγ.

    “This suggests that mechanisms reducing intracellular Fe availability in Mø have a dual role, limiting microbial access to intracellular Fe while boosting antimicrobial resistance mechanisms in response to cytokines such as IFNc [6].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Nairz M, Haschka D, Demetz E, Weiss G (2014) Iron at the interface of immunity and infection. Front Pharmacol 5: 152 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The cytotoxic effect of labile heme promotes tissue damage and compromises disease tolerance to malaria and severe sepsis.

    “Presumably, it is this cytotoxic effect that promotes tissue damage and hence compromises disease tolerance to malaria and severe sepsis [103,105,190].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [103] Ferreira A, Marguti I, Bechmann I, Jeney V, Chora A, Palha NR, Rebelo S, Henri A, Beuzard Y, Soares MP (2011) Sickle hemoglobin confers tolerance to plasmodium infection. Cell 145: 398–409 source

      Not checked in the free run.

    • cites [105] Pamplona A, Ferreira A, Balla J, Jeney V, Balla G, Epiphanio S, Chora A, Rodrigues CD, Gregoire IP, Cunha‐Rodrigues M et al (2007) Heme oxygenase‐1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat Med 13: 703–710 source

      Not checked in the free run.

    • cites [190] Larsen R, Gozzelino R, Jeney V, Tokaji L, Bozza FA, Japiassú AM, Bonaparte D, Cavalcante MM, Chora A, Ferreira A et al (2010) A central role for free heme in the pathogenesis of severe sepsis. Sci Transl Med 2: 51ra71 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This pro-oxidant effect blunts redox-sensitive phosphatases controlling JNK activation, inducing programmed cell death in response to TNF.

    “This pro-oxidant effect blunts the activity of redoxsensitive phosphatases controlling JNK activation [213,214], thus inducing programmed cell death in response to TNF [107,213,215].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [213] Pham CG, Bubici C, Zazzeroni F, Papa S, Jones J, Alvarez K, Jayawardena S, De Smaele E, Cong R, Beaumont C et al (2004) Ferritin heavy chain upregulation by NF‐kappaB inhibits TNFalpha‐induced apoptosis by suppressing reactive oxygen species. Cell 119: 529–542 source

      Not checked in the free run.

    • cites [214] Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M (2005) Reactive oxygen species promote TNFalpha‐induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120: 649–661 source

      Not checked in the free run.

    • cites [107] Gozzelino R, Andrade BB, Larsen R, Luz NF, Vanoaica L, Seixas E, Coutinho A, Cardoso S, Rebelo S, Poli M et al (2012) Metabolic adaptation to tissue iron overload confers tolerance to malaria. Cell Host Microbe 12: 693–704 source

      Not checked in the free run.

    • cites [215] Berberat PO, Katori M, Kaczmarek E, Anselmo D, Lassman C, Ke B, Shen X, Busuttil RW, Yamashita K, Csizmadia E et al (2003) Heavy chain ferritin acts as an antiapoptotic gene that protects livers from ischemia reperfusion injury. FASEB J 17: 1724–1726 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Heme overrides the cytoprotective program set in motion by NF-κB, which prevents sustained JNK activation and programmed cell death.

    “Heme overrides the cytoprotective program set in motion by the transcription factor NF-jB [209], which prevents sustained JNK activation and programmed cell death [210,211].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [209] Beg AA, Baltimore D (1996) An essential role for NF‐kappaB in preventing TNF‐alpha‐induced cell death. Science 274: 782–784 source

      Not checked in the free run.

    • cites [210] Tang G, Minemoto Y, Dibling B, Purcell NH, Li Z, Karin M, Lin A (2001) Inhibition of JNK activation through NF‐kappaB target genes. Nature 414: 313–317 source

      Not checked in the free run.

    • cites [211] Bubici C, Papa S, Pham CG, Zazzeroni F, Franzoso G (2006) The NF‐kappaB‐mediated control of ROS and JNK signaling. Histol Histopathol 21: 69–80

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The pathogenic effects of extracellular hemoglobin and labile heme are countered by adaptive responses converging on heme catabolism by HO-1, providing tissue damage control and disease tolerance to systemic infections.

    “The pathogenic effects exerted by extracellular hemoglobin and labile heme are countered by adaptive responses that converge at the level of heme catabolism by HO-1 [38,219], providing tissue damage control and disease tolerance to systemic infections [103,105,106] (Fig 4).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [38] Gozzelino R, Jeney V, Soares MP (2010) Mechanisms of cell protection by heme oxygenase‐1. Annu Rev Pharmacol Toxicol 50: 323–354 source

      Not checked in the free run.

    • cites [219] Soares MP, Marguti I, Cunha A, Larsen R (2009) Immunoregulatory effects of HO‐1: how does it work? Curr Opin Pharmacol 9: 482–489 source

      Not checked in the free run.

    • cites [103] Ferreira A, Marguti I, Bechmann I, Jeney V, Chora A, Palha NR, Rebelo S, Henri A, Beuzard Y, Soares MP (2011) Sickle hemoglobin confers tolerance to plasmodium infection. Cell 145: 398–409 source

      Not checked in the free run.

    • cites [105] Pamplona A, Ferreira A, Balla J, Jeney V, Balla G, Epiphanio S, Chora A, Rodrigues CD, Gregoire IP, Cunha‐Rodrigues M et al (2007) Heme oxygenase‐1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat Med 13: 703–710 source

      Not checked in the free run.

    • cites [106] Seixas E, Gozzelino R, Chora A, Ferreira A, Silva G, Larsen R, Rebelo S, Penido C, Smith NR, Coutinho A et al (2009) Heme oxygenase‐1 affords protection against noncerebral forms of severe malaria. Proc Natl Acad Sci USA 106: 15837–15842 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HO-1 avoids tissue Fe overload and tissue damage while sustaining Fe supply to erythropoiesis to maintain Fe homeostasis during infection.

    “When coupled to other mechanisms regulating Fe homeostasis, HO-1 avoids tissue Fe overload and tissue damage while sustaining Fe supply to erythropoiesis to maintain Fe homeostasis during infection [38,54,219,220] (Fig 4).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [38] Gozzelino R, Jeney V, Soares MP (2010) Mechanisms of cell protection by heme oxygenase‐1. Annu Rev Pharmacol Toxicol 50: 323–354 source

      Not checked in the free run.

    • cites [54] Gozzelino R, Soares MP (2014) Coupling heme and iron metabolism via ferritin H chain. Antioxid Redox Signal 20: 1754–1769 source

      Not checked in the free run.

    • cites [219] Soares MP, Marguti I, Cunha A, Larsen R (2009) Immunoregulatory effects of HO‐1: how does it work? Curr Opin Pharmacol 9: 482–489 source

      Not checked in the free run.

    • cites [220] Soares MP, Bach FH (2009) Heme oxygenase‐1: from biology to therapeutic potential. Trends Mol Med 15: 50–58 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Heme sensitizes cells to undergo apoptosis, as indicated by partial suppression of heme sensitization by caspase inhibition.

    “Heme sensitization to programmed cell death is partially suppressed by pharmacologic inhibition of caspases [106,107], indicating that heme sensitizes cells to undergo apoptosis [216].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [106] Seixas E, Gozzelino R, Chora A, Ferreira A, Silva G, Larsen R, Rebelo S, Penido C, Smith NR, Coutinho A et al (2009) Heme oxygenase‐1 affords protection against noncerebral forms of severe malaria. Proc Natl Acad Sci USA 106: 15837–15842 source

      Not checked in the free run.

    • cites [107] Gozzelino R, Andrade BB, Larsen R, Luz NF, Vanoaica L, Seixas E, Coutinho A, Cardoso S, Rebelo S, Poli M et al (2012) Metabolic adaptation to tissue iron overload confers tolerance to malaria. Cell Host Microbe 12: 693–704 source

      Not checked in the free run.

    • cites [216] Ellis HM, Horvitz HR (1986) Genetic control of programmed cell death in the nematode C. elegans. Cell 44: 817–829 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Labile heme impairs disease tolerance to systemic infections, as its pathogenic effect can be dissociated from host pathogen burden.

    “The pathogenic effect of labile heme can be dissociated from the host's pathogen burden [103,105,190], suggesting that labile heme impairs disease tolerance to these systemic infections.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [103] Ferreira A, Marguti I, Bechmann I, Jeney V, Chora A, Palha NR, Rebelo S, Henri A, Beuzard Y, Soares MP (2011) Sickle hemoglobin confers tolerance to plasmodium infection. Cell 145: 398–409 source

      Not checked in the free run.

    • cites [105] Pamplona A, Ferreira A, Balla J, Jeney V, Balla G, Epiphanio S, Chora A, Rodrigues CD, Gregoire IP, Cunha‐Rodrigues M et al (2007) Heme oxygenase‐1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat Med 13: 703–710 source

      Not checked in the free run.

    • cites [190] Larsen R, Gozzelino R, Jeney V, Tokaji L, Bozza FA, Japiassú AM, Bonaparte D, Cavalcante MM, Chora A, Ferreira A et al (2010) A central role for free heme in the pathogenesis of severe sepsis. Sci Transl Med 2: 51ra71 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Sickle hemoglobin mutations confer disease tolerance to malaria, as the protective effect is not associated with modulation of host pathogen load.

    “This protective effect is not associated with modulation of host pathogen load, revealing that sickle hemoglobin mutations confer disease tolerance to malaria [103,104].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [103] Ferreira A, Marguti I, Bechmann I, Jeney V, Chora A, Palha NR, Rebelo S, Henri A, Beuzard Y, Soares MP (2011) Sickle hemoglobin confers tolerance to plasmodium infection. Cell 145: 398–409 source

      Not checked in the free run.

    • cites [104] Ferreira A, Balla J, Jeney V, Balla G, Soares MP (2008) A central role for free heme in the pathogenesis of severe malaria: the missing link? J Mol Med 86: 1097–1111 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lactoferrin acts synergistically with antibiotics against Staphylococci infections and can control bovine mastitis.

    “Moreover, lactoferrin acts synergistically with antibiotics against Staphylococci infections and can be used to control bovine mastitis [234].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [234] Diarra MS, Petitclerc D, Lacasse P (2002) Effect of lactoferrin in combination with penicillin on the morphology and the physiology of Staphylococcus aureus isolated from bovine mastitis. J Dairy Sci 85: 1141–1149 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sickle hemoglobin mutations induce labile heme generation, which triggers Nrf2 activation and expression of [something].

    “Namely, sickle hemoglobin mutations induce the generation of labile heme, which triggers the activation of the transcription factor Nrf2 and the expression of 104].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Ferreira A, Balla J, Jeney V, Balla G, Soares MP (2008) A central role for free heme in the pathogenesis of severe malaria: the missing link? J Mol Med 86: 1097–1111 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Systemic Fe chelation by desferrioxamine can improve the clinical course of malaria, without providing an overt survival benefit.

    “Systemic Fe chelation by desferrioxamine can improve the clinical course of malaria, without, however, providing an overt survival benefit [236].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [236] Gordeuk V, Thuma P, Brittenham G, McLaren C, Parry D, Backenstose A, Biemba G, Msiska R, Holmes L, McKinley E et al (1992) Effect of iron chelation therapy on recovery from deep coma in children with cerebral malaria. N Engl J Med 327: 1473–1477 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Fe chelator desferasirox improves survival of infected mice, limiting Fe availability to the pathogen while enhancing host resistance.

    “However, the Fe chelator desferasirox, which cannot be used by molds to acquire Fe, improves survival of infected mice, limiting Fe availability to the pathogen while enhancing host resistance mechanisms [238].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [238] Ibrahim AS, Gebermariam T, Fu Y, Lin L, Husseiny MI, French SW, Schwartz J, Skory CD, Edwards JE Jr, Spellberg BJ (2007) The iron chelator deferasirox protects mice from mucormycosis through iron starvation. J Clin Invest 117: 2649–2657 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CO modulates signaling by PRRs, inhibiting TNF while increasing IL-10 secretion by activated Mø.

    “In addition, CO modulates signaling by PRRs, as illustrated for TLR4, inhibiting TNF while increasing IL-10 secretion by activated Mø [225].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [225] Otterbein LE, Bach FH, Alam J, Soares MP, Tao HL, Wysk M, Davis R, Flavell R, Choi AMK (2000) Carbon monoxide mediates anti‐inflammatory effects via the mitogen activated protein kinase pathway. Nat Med 6: 422–428 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The protective effects of FTH do not interfere with host pathogen burden, illustrating that regulation of host Fe metabolism confers disease tolerance to infection.

    “The protective effects of FTH do not interfere with host pathogen burden, illustrating further how regulation of host Fe metabolism confers disease tolerance to infection [103,106,190].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [103] Ferreira A, Marguti I, Bechmann I, Jeney V, Chora A, Palha NR, Rebelo S, Henri A, Beuzard Y, Soares MP (2011) Sickle hemoglobin confers tolerance to plasmodium infection. Cell 145: 398–409 source

      Not checked in the free run.

    • cites [106] Seixas E, Gozzelino R, Chora A, Ferreira A, Silva G, Larsen R, Rebelo S, Penido C, Smith NR, Coutinho A et al (2009) Heme oxygenase‐1 affords protection against noncerebral forms of severe malaria. Proc Natl Acad Sci USA 106: 15837–15842 source

      Not checked in the free run.

    • cites [190] Larsen R, Gozzelino R, Jeney V, Tokaji L, Bozza FA, Japiassú AM, Bonaparte D, Cavalcante MM, Chora A, Ferreira A et al (2010) A central role for free heme in the pathogenesis of severe sepsis. Sci Transl Med 2: 51ra71 source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    Hepcidin-induced hypoferremia is a critical host defense mechanism against Vibrio vulnificus in mice.

    “The proof of principle for this approach was provided for Vibrio vulnificus infection in mice [96].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [96] Arezes J, Jung G, Gabayan V, Valore E, Ruchala P, Gulig PA, Ganz T, Nemeth E, Bulut Y (2015) Hepcidin‐induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium Vibrio vulnificus. Cell Host Microbe 17: 47–57 source

      Not checked in the free run.

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

    Premisenone given

    Tf transports and provides Fe to the erythropoietic compartment via TfR, where it is used for heme synthesis.

    “Tf transports and provides Fe to the erythropoietic compartment via TfR, where it is used for heme synthesis (bottom right).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Immune responses to extracellular pathogens encompass production of cytokines IL-1, IL-6, and IL-22, which induce transcription of the hepcidin (HAMP) gene in hepatocytes.

    “Immune responses to extracellular pathogens encompass the production of cytokines, for example, IL-1, IL-6, and IL-22, which induce the transcription of the hepcidin (HAMP) gene in hepatocytes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Oxidized extracellular hemoglobin can release heme, which acts as a pro-inflammatory agonist in endothelial cells and Mø via TLR4, or via GPCRs in PMN cells.

    “Oxidized extracellular hemoglobin can also release heme, which acts as a pro-inflammatory agonist in endothelial cells and Mø via TLR4, or via GPCRs in PMN cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Extracellular hemoglobin can scavenge NO, promoting vasoconstriction and affecting microvascular circulation.

    “For example, extracellular hemoglobin can scavenge NO, promoting vasoconstriction and eventually affecting microvascular circulation (top).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Pathogen class-specific strategies evolved to control Fe and heme availability to intracellular versus extracellular pathogens.

    “This relationship is complex and pathogen class-specific strategies evolved to control Fe and heme availability to intracellular versus extracellular pathogens.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    CO is a potent cytoprotective molecule that prevents tissue damage and can enforce disease tolerance to infection.

    “Finally, CO is a potent cytoprotective molecule that prevents tissue damage and as such can enforce disease tolerance to infection.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    IFNγR signaling also inhibits Fe extracellular uptake via TfR.

    “IFNcR signaling also inhibits Fe extracellular uptake via TfR.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Labile heme sensitizes parenchyma cells to undergo programmed cell death in response to TNF, leading to tissue damage and compromising disease tolerance.

    “Labile heme sensitizes parenchyma cells to undergo programmed cell death in response to TNF, leading to tissue damage and compromising disease tolerance (right).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Circulating hepcidin targets FPN for degradation, inhibiting Fe cellular retention in many cell types, including Mø.

    “Circulating hepcidin targets systemically the Fe export protein FPN for degradation, which inhibits Fe cellular retention in many cell types, including Mø, which are pivotal to the maintenance of Fe homeostasis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Mø can engulf damaged RBC and prevent hemoglobin release or scavenge extracellular hemoglobin/haptoglobin via CD163 as well as heme/HPX complexes via CD91.

    “In addition, Mø can engulf damaged RBC and prevent hemoglobin release or (H) scavenge extracellular hemoglobin/haptoglobin via the scavenger receptor CD163 as well as (I) heme/HPX complexes via the scavenger receptor CD91.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Lcn2 neutralizes the action of bacterial siderophores.

    “Lcn2 neutralizes the action of bacterial siderophores.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Pathogen virulence often emerges via natural selection of genes that favor Fe and/or heme uptake by microbes.

    “Pathogen virulence often emerges via natural selection of genes that favor Fe and/or heme uptake by microbes, suggesting that targeting such mechanisms may be of therapeutic value to combat infectious diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Ferritin stores intracellular Fe and FPN delivers Fe to Tf and supports erythropoiesis.

    “These include ferritin, which stores intracellular Fe and FPN, which delivers Fe to Tf and supports erythropoiesis.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    Heme synthesis occurs via eight successive enzymatic reactions in mitochondria and cytosol.

    “Heme synthesis occurs via eight successive enzymatic reactions that take place back and forward in the mitochondria (brown) and the cytosol (blue).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The Fe required to sustain hemoglobin synthesis is made available by hemophagocytic Mø as these clear senescent RBC by erythrophagocytosis.

    “The Fe required to sustain hemoglobin synthesis is made available by hemophagocytic Mø as these clear senescent RBC by erythrophagocytosis (top right)[49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Korolnek T, Hamza I (2015) Macrophages and iron trafficking at the birth and death of red cells. Blood 125: 2893–2897 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    HO-1 enzymatic activity generates CO, which promotes secretion of IL-10 in activated Mø, impacting MHC class II/TCR-driven activation of TH cells and contributing to tissue damage control and disease tolerance.

    “Moreover, HO-1 enzymatic activity generates CO, which promotes the secretion of IL-10 in activated Mø, impacting on MHC class II/TCR-driven activation of T H cells and thereby contributing to tissue damage control and eventually to disease tolerance (middle).”
    Quote in the paperSubstantial claim

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

    Premisenone given

    The heme contained in hemoglobin is transported by HRG1 into the cytoplasm where Fe is extracted by HO-1, exported via FPN, and delivered to Tf in plasma.

    “The heme contained in hemoglobin is transported by heme-responsive gene-1 (HRG1) into the cytoplasm where Fe is extracted by hemeoxygnease-1 (HO-1), exported via ferroportin (FPN), and delivered to traferrin (Tf) in plasma.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Uptake of heme/HPX, damaged RBC, or hemoglobin/haptoglobin by Mø is coupled to heme transport from phagolysomes to cytoplasm by HRG1, and to heme catabolism by HO-1.

    “Uptake of heme/HPX, damaged RBC, or hemoglobin/haptoglobin by Mø is coupled to heme transport from phagolysomes to the cytoplasm, by the heme transporter HRG1, and to heme catabolism by HO-1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    This prevents anemia and tissue hypoxia, an effect likely to promote disease tolerance.

    “This prevents anemia and tissue hypoxia, an effect likely to promote disease tolerance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Cellular Fe retention by Mø can lead to anemia of inflammation, which triggers production of hormones such as Epo, Erfe, GDF15, PDGF-BB, or activation of HIF family, which reduce hepcidin expression.

    “Cellular Fe retention by Mø can lead to the development of anemia of inflammation, which triggers the production of several hormones, such as Epo, Erfe, GDF15, PDGF-BB, or the activation of the HIF family of transcription factors, which reduce hepcidin expression.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Lactoferrin binds Fe and limits its availability to bacteria.

    “Lactoferrin binds Fe and limits its availability to bacteria.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Surplus cytoplasmic Fe in Mø is incorporated and stored within ferritin.

    “Surplus cytoplasmic Fe in Mø is incorporated and stored within ferritin.”
    Quote in the paperNot a substantial claim
85 of 85

  • The paper relies on this without support.

    There is an urgent need for alternative treatment strategies to cope with rising microbial resistance to antimicrobial drugs.

    “There is an urgent need of alternative treatment strategies that can cope with the recent raise of microbial resistance to antimicrobial drugs.”
1 of 1

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?

  • In the adaptive immune system, iron is an essential growth factor for the clonal expansion of lymphocyte subsets.

    “In the adaptive immune system, iron is an essential growth-factor for the clonal expansion of lymphocyte subsets (Ganz and Nemeth, 2015;Soares and Weiss, 2015;Weiss, 2002).”

    From Iron in infection and immunity (2020) · cites this paper as Soares and Weiss, 2015

    In “Regulation of Fe metabolism by macrophages during infection” (page unavailable), the review says iron content affects TH1-cell activation and proliferation, and that blocking iron import inhibits TH1 responses. It also says TH2 cells are less sensitive. This supports a role for iron in T-cell responses, but not the broader claim that iron is an essential growth factor for the clonal expansion of lymphocyte subsets generally. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Iron trafficking is controlled by cytokines and acute phase proteins, whereas iron promotes lymphocyte and macrophage differentiation, anti-microbial immune effector function, and immune cell metabolism.

    “Accordingly, iron trafficking is controlled by cytokines and acute phase proteins, whereas the metal itself promotes lymphocyte and macrophage differentiation, anti-microbial immune effector function, and immune cell metabolism, as we will discuss later (Ganz and Nemeth, 2015; Soares and Weiss, 2015).”

    From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Soares and Weiss, 2015

  • Iron trafficking during infections is differently regulated, depending on the nature and cellular localization (intra- vs. extra-cellular) of the pathogen.

    “However, iron trafficking during infections is differently regulated, depending on the nature and cellular localization, intra- vs. extra-cellular, of the pathogen (Drakesmith and Prentice, 2012; Soares and Weiss, 2015).”

    From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Soares and Weiss, 2015

  • Iron-related immune effects are specifically fine-tuned depending on the nature and cellular localization of the pathogen and on the tissues and specific cells involved in infection.

    “These effects appear to be very specifically fine-tuned depending on the nature and cellular localization of the respective pathogen as well in regards to the tissues and specific cells being involved in infection [155,180,181].”

    From Iron in immune cell function and host defense (2021) · cites this paper as [180]

  • Competition for limited iron became a conserved host defense against infection in plants and animals and also a microbial virulence factor.

    “where competition for limited Fe resources emerged as an evolutionary conserved host defense strategy against infection in plants (2) and animals (3–5) as well as a microbial virulence factor (6).”

    From Innate Nutritional Immunity (2018) · cites this paper as [5]

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.

  • Figure 2 reverses hepcidin's stated effect on iron retention

    Minor

    The figure caption says that hepcidin-driven FPN degradation inhibits cellular iron retention. Elsewhere, the paper says that hepcidin's action on FPN causes intracellular iron accumulation.

  • Heme-synthesis steps name incompatible pathway intermediates

    Minor

    The stated sequence proceeds through the I forms of uroporphyrinogen and coproporphyrinogen, but the next steps instead use the III forms without describing a change between them.

2 of 2

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Related

Authors
Soares, M. P., & Weiss, G.
Affiliations
  • Instituto Gulbenkian de Ciência (PT)
  • Innsbruck Medical University (AT)
Corresponding author
  • Soares, Miguel P
  • Weiss, Günter
ORCID
Venue
The EMBO Reports
Publisher
Springer Science and Business Media LLC
Published
2015-10-16
Volume
16
Issue
11
Pages
1482-1500
ISSN
  • 1469-221X (ISSN-L)
  • 1469-3178
DOI
10.15252/embr.201540558
PMC
PMC4641501
OpenAlex
W2160852190
Cited by
227
References
249
Citations by year
2026: 17 · 2025: 23 · 2024: 14 · 2023: 20 · 2022: 19 · 2021: 19 · 2020: 28 · 2019: 29 · 2018: 20 · 2017: 25 · 2016: 12 · 2015: 1
FWCI
2.94
Type
journal article
Language
en
Open access
Licence
Locations
  • EMBO Reports (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Fundação para a Ciência e Tecnologia
  • PTDC/SAU (TOX/116627/2010, HMSP‐ICT/0022/2010)
  • European Community 7th Framework (ERC‐2011‐AdG, 294709–DAMAGECONTROL)
  • Austrian Research fund (FWF‐TRP‐188)
  • Eurocalin
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Keywords
host-microbe interactions, iron metabolism, host defense, disease resistance, disease tolerance, host homeostasis, microbial pathogenicity, iron regulation, infection
MeSH terms
Anemia, Chronic Disease, Heme, Homeostasis, Humans, Infections, Iron, Macrophages, Host-Pathogen Interactions, Disease Resistance

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 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

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