The Iron age of host–microbe interactions

In the paper

“while dietary Fe supplementation exacerbates the overall rate of mortality in areas endemic for such infectious diseases [23][24][25][26][27].”

What the sources say

• Not checked yetcites [23] Esan MO, van Hensbroek MB, Nkhoma E, Musicha C, White SA, Ter Kuile FO, Phiri KS (2013) Iron supplementation in HIV‐infected Malawian children with anemia: a double‐blind, randomized, controlled trial. Clin Infect Dis 57: 1626–1634 source
• Not checked yetcites [24] Prentice AM, Verhoef H, Cerami C (2013) Iron fortification and malaria risk in children. JAMA 310: 914–915 source
• Not checked yetcites [25] Zlotkin S, Newton S, Aimone AM, Azindow I, Amenga‐Etego S, Tchum K, Mahama E, Thorpe KE, Owusu‐Agyei S (2013) Effect of iron fortification on malaria incidence in infants and young children in Ghana: a randomized trial. JAMA 310: 938–947 source

In the paper

“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].”

What the sources say

• Not checked yetcites [5] Weinberg ED (2009) Iron availability and infection. Biochim Biophys Acta 1790: 600–605 source
• Not checked yetcites [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 yetcites [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
• Not checked yetcites [30] Contreras H, Chim N, Credali A, Goulding CW (2014) Heme uptake in bacterial pathogens. Curr Opin Chem Biol 19: 34–41 source

In the paper

“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]”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [34] Barber MF, Elde NC (2014) Nutritional immunity. Escape from bacterial iron piracy through rapid evolution of transferrin. Science 346: 1362–1366 source

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [80] Bogdan C (2001) Nitric oxide and the immune response. Nat Immunol 2: 907–916 source
• Not checked yetcites [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 yetcites [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

In the paper

“The microbicidal activity of activated Mø depends critically on the phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2/gp91 phox ) and the inducible form of nitric oxide (NO) synthase (iNOS/NOS2) [74,75].”

What the sources say

• Not checked yetcites [74] Vazquez‐Torres A, Jones‐Carson J, Mastroeni P, Ischiropoulos H, Fang FC (2000) Antimicrobial actions of the NADPH phagocyte oxidase and inducible nitric oxide synthase in experimental salmonellosis. I. Effects on microbial killing by activated peritoneal macrophages in vitro. J Exp Med 192: 227–236 source
• Not checked yetcites [75] Mastroeni P, Vazquez‐Torres A, Fang FC, Xu Y, Khan S, Hormaeche CE, Dougan G (2000) Antimicrobial actions of the NADPH phagocyte oxidase and inducible nitric oxide synthase in experimental salmonellosis. II. Effects on microbial proliferation and host survival in vivo. J Exp Med 192: 237–248 source

In the paper

“Monocytes/macrophages (Mø) play a central role in the maintenance of Fe homeostasis, delivering approximately 95% of the Fe required to support de novo heme/hemoglobin synthesis during erythropoiesis [48,49] (Fig 1).”

What the sources say

• Not checked yetcites [48] Nairz M, Schroll A, Demetz E, Tancevski I, Theurl I, Weiss G (2015) ‘Ride on the ferrous wheel’–the cycle of iron in macrophages in health and disease. Immunobiology 220: 280–294 source
• Not checked yetcites [49] Korolnek T, Hamza I (2015) Macrophages and iron trafficking at the birth and death of red cells. Blood 125: 2893–2897 source

In the paper

“Induction of hypoferremia, via systemic inhibition of extracellular Fe export coupled to increased Mø Fe/heme uptake and intracellular retention [5,6], reduces the growth and virulence of extracellular pathogens, as illustrated for Vibrio vulnificus infection in mice [96,97].”

What the sources say

• Not checked yetcites [5] Weinberg ED (2009) Iron availability and infection. Biochim Biophys Acta 1790: 600–605 source
• Not checked yetcites [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 yetcites [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 yetcites [97] Bullen JJ, Spalding PB, Ward CG, Gutteridge JM (1991) Hemochromatosis, iron and septicemia caused by Vibrio vulnificus. Arch Intern Med 151: 1606–1609 source

In the paper

“This argues that expression of these enzymes must be functionally integrated with mechanisms regulating Fe-heme metabolism as to support their activity and hence Mø microbicidal activity.”

In the paper

“Of note, deletion of genes regulating the expression of siderophores or other Fe uptake systems is often associated with reduced pathogen virulence, as illustrated for bacteria, for example, Staphylococci and Salmonella, or fungi, for example, Aspergillus, infections [6,7,32,33].”

What the sources say

• Not checked yetcites [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 yetcites [7] Cassat JE, Skaar EP (2013) Iron in infection and immunity. Cell Host Microbe 13: 509–519 source
• Not checked yetcites [32] Andrews‐Polymenis HL, Baumler AJ, McCormick BA, Fang FC (2010) Taming the elephant: salmonella biology, pathogenesis, and prevention. Infect Immun 78: 2356–2369 source
• Not checked yetcites [33] Schrettl M, Bignell E, Kragl C, Joechl C, Rogers T, Arst HN Jr, Haynes K, Haas H (2004) Siderophore biosynthesis but not reductive iron assimilation is essential for Aspergillus fumigatus virulence. J Exp Med 200: 1213–1219 source

In the paper

“This is probably the case for haptoglobin (HP) and hemopexin (HPX), two acute-phase proteins that scavenge extracellular hemoglobin and labile heme in plasma, respectively [39].”

What the sources say

• Not checked yetcites [39] Ascenzi P, Bocedi A, Visca P, Altruda F, Tolosano E, Beringhelli T, Fasano M (2005) Hemoglobin and heme scavenging. IUBMB Life 57: 749–759 source

In the paper

“That these genes modulate the pathogenesis of infectious diseases in humans is supported by the association of polymorphisms in the human HP genes with an unfavorable course of co-infections resulting from HIV-driven immunodeficiency [41], malaria [42], or tuberculosis [43].”

What the sources say

• Not checked yetcites [41] Delanghe JR, Langlois MR, Boelaert JR, Van Acker J, Van Wanzeele F, van der Groen G, Hemmer R, Verhofstede C, De Buyzere M, De Bacquer D et al (1998) Haptoglobin polymorphism, iron metabolism and mortality in HIV infection. AIDS 12: 1027–1032 source
• Not checked yetcites [42] Quaye IK, Ekuban FA, Goka BQ, Adabayeri V, Kurtzhals JA, Gyan B, Ankrah NA, Hviid L, Akanmori BD (2000) Haptoglobin 1‐1 is associated with susceptibility to severe Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg 94: 216–219 source
• Not checked yetcites [43] Kasvosve I, Gomo ZA, Mvundura E, Moyo VM, Saungweme T, Khumalo H, Gordeuk VR, Boelaert JR, Delanghe JR, De Bacquer D et al (2000) Haptoglobin polymorphism and mortality in patients with tuberculosis. Int J Tuberc Lung Dis 4: 771–775

In the paper

“More recently, an association between plasma levels of HO-1 and active versus latent or treated pulmonary tuberculosis has been established [47].”

What the sources say

• Not checked yetcites [47] Andrade BB, Pavan Kumar N, Mayer‐Barber KD, Barber DL, Sridhar R, Rekha VV, Jawahar MS, Nutman TB, Sher A, Babu S (2013) Plasma heme oxygenase‐1 levels distinguish latent or successfully treated human tuberculosis from active disease. PLoS ONE 8: e62618 source

In the paper

“This suggests that host adaptive responses regulating heme metabolism and depriving microbes from accessing this source of Fe can exert a major impact on the outcome of infectious diseases.”

In the paper

“Moreover, heme catabolism by heme oxygenase-1 (HO-1), a stress-responsive enzyme that converts labile heme into equimolar amounts of Fe, carbon monoxide (CO), and biliverdin [40], should also contribute to deprive microbes from accessing Fe contained in heme.”

What the sources say

• Not checked yetcites [40] Tenhunen R, Marver HS, Schmid R (1968) The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci USA 61: 748 source

In the paper

“Taken together, these observations argue that regulation of Mø intracellular Fe content impacts on resistance to infection.This effect goes beyond secluding Fe from invading pathogens, encompassing the modulation of innate and adaptive immune responses against those pathogens.”

In the paper

“Specifically, the intracellular Fe content of Mø modulates their response to interferon c (IFNc) [68,69], a cytokine produced by activated natural killer (NK) cells and T helper type 1 (T H 1) cells, which plays a central role in driving Mø microbicidal activity [70].”

What the sources say

• Not checked yetcites [68] Weiss G, Fuchs D, Hausen A, Reibnegger G, Werner ER, Werner‐Felmayer G, Wachter H (1992) Iron modulates interferon‐gamma effects in the human myelomonocytic cell line THP‐1. Exp Hematol 20: 605–610
• Not checked yetcites [69] Mencacci A, Cenci E, Boelaert JR, Bucci P, Mosci P, Fe d'Ostiani C, Bistoni F, Romani L (1997) Iron overload alters innate and T helper cell responses to Candida albicans in mice. J Infect Dis 175: 1467–1476 source
• Not checked yetcites [70] Nathan CF, Murray HW, Wiebe ME, Rubin BY (1983) Identification of interferon‐gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J Exp Med 158: 670–689 source

In the paper

“Cytokine-driven NF-jB activation induces FTH transcription, supporting further retention of Fe in Mø [54,55] (Fig 2).”

What the sources say

• Not checked yetcites [54] Gozzelino R, Soares MP (2014) Coupling heme and iron metabolism via ferritin H chain. Antioxid Redox Signal 20: 1754–1769 source
• Not checked yetcites [55] Harrison PM, Arosio P (1996) Ferritins ‐ molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta ‐ Bioenergetics 1275: 161–203 source

In the paper

“Other cytokines such as IL-4, IL-10, and IL-13 promote TfRmediated Fe uptake and intracellular retention by ferritin [113].”

What the sources say

• Not checked yetcites [113] Weiss G, Schett G (2013) Anaemia in inflammatory rheumatic diseases. Nat Rev Rheumatol 9: 205–215 source

In the paper

“The impact of such pathogen class-specific mechanisms is particularly relevant in the context of co-infections, where restricting Fe access to one pathogen can be detrimental against co-infection by another pathogen.”

In the paper

“However, while this may provide a fast acting strategy to limit Mø Fe export, sustained Fe retention requires additional inputs provided by cytokines such as IFNc, which represses FPN transcription [6] (Fig 2).”

What the sources say

• Not checked yetcites [6] Nairz M, Haschka D, Demetz E, Weiss G (2014) Iron at the interface of immunity and infection. Front Pharmacol 5: 152 source

In the paper

“The Fe-binding capacity of lactoferrin can also interfere with microbial virulence pathways such as biofilm formation [122].”

What the sources say

• Not checked yetcites [122] Singh PK, Parsek MR, Greenberg EP, Welsh MJ (2002) A component of innate immunity prevents bacterial biofilm development. Nature 417: 552–555 source

In the paper

“Cellular internalization of Fe-loaded lactoferrin by Mø can lead to cellular Fe overload and cytotoxicity [124].”

What the sources say

• Not checked yetcites [124] Crouch SP, Slater KJ, Fletcher J (1992) Regulation of cytokine release from mononuclear cells by the iron‐binding protein lactoferrin. Blood 80: 235–240 source

In the paper

“Moreover, lactoferrin modulates the activation and proliferation of lymphocytes, NK cells, and Mø, via a mechanism mediated in part by lactoferrin receptors expressed by these cells [117,123].”

What the sources say

• Not checked yetcites [117] Brock JH (2002) The physiology of lactoferrin. Biochem Cell Biol 80: 1–6 source
• Not checked yetcites [123] Bullen JJ, Rogers HJ, Spalding PB, Ward CG (2006) Natural resistance, iron and infection: a challenge for clinical medicine. J Med Microbiol 55: 251–258 source

In the paper

“Lcn2 also promotes resistance to non-bacterial pathogens, as demonstrated for Plasmodium infection [133].”

What the sources say

• Not checked yetcites [133] Zhao H, Konishi A, Fujita Y, Yagi M, Ohata K, Aoshi T, Itagaki S, Sato S, Narita H, Abdelgelil NH et al (2012) Lipocalin 2 bolsters innate and adaptive immune responses to blood‐stage malaria infection by reinforcing host iron metabolism. Cell Host Microbe 12: 705–716 source

In the paper

“Activated Mø can produce minute amounts of hepcidin in response to bacterial lipopolysaccharide (LPS) or cytokines, targeting FPN for proteolytic degradation [109,110].”

What the sources say

• Not checked yetcites [109] Peyssonnaux C, Zinkernagel AS, Datta V, Lauth X, Johnson RS, Nizet V (2006) TLR4‐dependent hepcidin expression by myeloid cells in response to bacterial pathogens. Blood 107: 3727–3732 source
• Not checked yetcites [110] Theurl I, Theurl M, Seifert M, Mair S, Nairz M, Rumpold H, Zoller H, Bellmann‐Weiler R, Niederegger H, Talasz H et al (2008) Autocrine formation of hepcidin induces iron retention in human monocytes. Blood 111: 2392–2399 source

In the paper

“However, this strategy can be detrimental against intracellular pathogens, enhancing their growth and proliferation, as illustrated for bacteria from Chlamydia, Legionella, Salmonella, and Mycobacteria spp.[98][99][100][101][102].”

What the sources say

• Not checked yetcites [98] Chlosta S, Fishman DS, Harrington L, Johnson EE, Knutson MD, Wessling‐Resnick M, Cherayil BJ (2006) The iron efflux protein ferroportin regulates the intracellular growth of Salmonella enterica. Infect Immun 74: 3065–3067 source
• Not checked yetcites [99] Paradkar PN, De Domenico I, Durchfort N, Zohn I, Kaplan J, Ward DM (2008) Iron depletion limits intracellular bacterial growth in macrophages. Blood 112: 866–874 source
• Not checked yetcites [100] Nairz M, Theurl I, Ludwiczek S, Theurl M, Mair SM, Fritsche G, Weiss G (2007) The co‐ordinated regulation of iron homeostasis in murine macrophages limits the availability of iron for intracellular Salmonella typhimurium. Cell Microbiol 9: 2126–2140 source

In the paper

“This defense mechanism was also retained in arthropods, in which the hemoglobin functional homolog hemocyanin displays similar antimicrobial functions [138].”

What the sources say

• Not checked yetcites [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

In the paper

“The general strategy to restrict Fe access to intracellular pathogens consists in the induction of hyperferremia, driven by systemic induction of cellular Fe export coupled to the suppression of cellular Fe import systems from Mø as well as other cell types.”

In the paper

“Hemoglobin also enhances the pro-inflammatory activity of LPS [141].”

What the sources say

• Not checked yetcites [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

In the paper

“When expressed in phagosomes FPN can reduce Fe supply to pathogens in this subcellular compartment, as shown in vitro for Mycobacteria infection [101] (Fig 3).”

What the sources say

• Not checked yetcites [101] Van Zandt KE, Sow FB, Florence WC, Zwilling BS, Satoskar AR, Schlesinger LS, Lafuse WP (2008) The iron export protein ferroportin 1 is differentially expressed in mouse macrophage populations and is present in the mycobacterial‐containing phagosome. J Leukoc Biol 84: 689–700 source

In the paper

“Given the sheer number of RBCs (~2-3 × 10 13 in adult humans) and their extremely high hemoglobin (~3 × 10 8 molecules/RBC) and heme (~1.2 × 10 9 molecules/RBC) content, disruption of a relatively small numbers of RBCs is sufficient to release significant amounts of hemoglobin [49].”

What the sources say

• Not checked yetcites [49] Korolnek T, Hamza I (2015) Macrophages and iron trafficking at the birth and death of red cells. Blood 125: 2893–2897 source

In the paper

“Both ROS and RNS produced by activated Mø or PMN cells can elicit different forms of stress and damage to bystander red blood cells (RBC), eventually leading to the release of their hemoglobin content.”

In the paper

“Of interest, Mycobacteria avium can overcome Fe limitation by Lcn2 by residing in Rab11 + recycling phagosomes where the bacterium has access to transferrin Fe but avoids Fe restriction by Lcn2 [158].”

What the sources say

• Not checked yetcites [158] Halaas O, Steigedal M, Haug M, Awuh JA, Ryan L, Brech A, Sato S, Husebye H, Cangelosi GA, Akira S et al (2010) Intracellular Mycobacterium avium intersect transferrin in the Rab11(+) recycling endocytic pathway and avoid lipocalin 2 trafficking to the lysosomal pathway. J Infect Dis 201: 783–792 source

In the paper

“Nonetheless, induction of Lcn2 expression is also involved in the mechanism that protects mice lacking the hemochromatosis protein (HFE) from Salmonella infection [159].”

What the sources say

• Not checked yetcites [159] Nairz M, Theurl I, Schroll A, Theurl M, Fritsche G, Lindner E, Seifert M, Crouch ML, Hantke K, Akira S et al (2009) Absence of functional Hfe protects mice from invasive Salmonella enterica serovar Typhimurium infection via induction of lipocalin‐2. Blood 114: 3642–3651 source

In the paper

“Moreover, extracellular hemoglobin may also exert protective effects based on NO and ONNO À detoxification [76,80,197].”

What the sources say

• Not checked yetcites [76] Nathan C, Shiloh MU (2000) Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proc Natl Acad Sci USA 97: 8841–8848 source
• Not checked yetcites [80] Bogdan C (2001) Nitric oxide and the immune response. Nat Immunol 2: 907–916 source
• Not checked yetcites [197] Stamler JS (1994) Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell 78: 931–936 source

In the paper

“Labile heme plays a central role in the pathogenesis of severe forms of malaria as well as severe sepsis in mice [103,105,190].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“The clinical relevance of this pathologic process is strongly supported by the finding that accumulation of extracellular hemoglobin is associated with higher risk of death from severe sepsis [193,194].”

What the sources say

• Not checked yetcites [193] Janz DR, Bastarache JA, Peterson JF, Sills G, Wickersham N, May AK, Roberts LJ 2nd, Ware LB (2013) Association between cell‐free hemoglobin, acetaminophen, and mortality in patients with sepsis: an observational study. Crit Care Med 41: 784–790 source
• Not checked yetcites [194] Adamzik M, Hamburger T, Petrat F, Peters J, de Groot H, Hartmann M (2012) Free hemoglobin concentration in severe sepsis: methods of measurement and prediction of outcome. Crit Care 16: R125 source

In the paper

“Heme catabolism by HO-1 also supports resistance to intracellular bacteria, as suggested for Mycobacteria infection in mice [170,171].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“Accumulation of extracellular hemoglobin can exert pathogenic effects that foster the pathogenesis of infectious diseases, as illustrated for the development of severe sepsis in response to systemic polymicrobial infections in mice [190].”

What the sources say

• Not checked yetcites [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

In the paper

“Electron transfer from Fe 4+ can oxidize tyrosines in the globulin chains of hemoglobin, giving rise to dityrosine bonds that promote the generation of ferrylhemoglobin aggregates [198].”

What the sources say

• Not checked yetcites [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

In the paper

“such as PDGF-BB, also inhibit hepcidin transcription [64] (Fig 3).”

What the sources say

• Not checked yetcites [64] Sonnweber T, Nachbaur D, Schroll A, Nairz M, Seifert M, Demetz E, Haschka D, Mitterstiller AM, Kleinsasser A, Burtscher M et al (2014) Hypoxia induced downregulation of hepcidin is mediated by platelet derived growth factor BB. Gut 63: 1951–1959 source

In the paper

“This is also the case for the development of severe forms of malaria in response to Plasmodium infection in mice [103][104][105][106]191,192].”

What the sources say

• Not checked yetcites [103][104][105][106]191,192]

In the paper

“Sustained oxidation of extracellular hemoglobin dimers, such as driven by products of activated Mø and PMN cells, generates met(Fe 3+ ) and eventually ferryl(Fe 4+ )hemoglobin [198].”

What the sources say

• Not checked yetcites [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

In the paper

“The mechanisms underlying the pathogenic effects of extracellular hemoglobin were associated originally to NO scavenging, reducing NO bioavailability, and impairing microvascular homeostasis [192,196] (Fig 4).”

What the sources say

• Not checked yetcites [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 yetcites [196] Schaer DJ, Buehler PW, Alayash AI, Belcher JD, Vercellotti GM (2013) Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins. Blood 121: 1276–1284 source

In the paper

“Extracellular methemoglobin can release its non-covalently bound heme [38,104,105,190,[199][200][201], generating labile heme, that is, redox active heme that is loosely bound to plasma proteins or to other molecules (Fig 4).”

What the sources say

• Not checked yetcites [38,104,105,190,[199][200][201]

In the paper

“Moreover, reduced levels of the hemoglobin scavenger haptoglobin are also associated with increased malaria severity [195].”

What the sources say

• Not checked yetcites [195] Mendonca VR, Luz NF, Santos NJ, Borges VM, Goncalves MS, Andrade BB, Barral‐Netto M (2012) Association between the haptoglobin and heme oxygenase 1 genetic profiles and soluble CD163 in susceptibility to and severity of human malaria. Infect Immun 80: 1445–1454 source

In the paper

“This is in line with the finding that sustained JNK activation shifts TNF-mediated programmed cell death from apoptosis to necrosis [217,218] and that heme can trigger necroptosis in Mø, via an autocrine loop in which heme triggers the production of TNF upon the engagement of TLR4 [173].”

What the sources say

• Not checked yetcites [217] Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11: 700–714 source
• Not checked yetcites [218] Ventura JJ, Cogswell P, Flavell RA, Baldwin AS Jr, Davis RJ (2004) JNK potentiates TNF‐stimulated necrosis by increasing the production of cytotoxic reactive oxygen species. Genes Dev 18: 2905–2915 source

In the paper

“This is in line with the finding that sustained JNK activation shifts TNF-mediated programmed cell death from apoptosis to necrosis [217,218] and that heme can trigger necroptosis in Mø, via an autocrine loop in which heme triggers the production of TNF upon the engagement of TLR4 [173].”

What the sources say

• Not checked yetcites [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

In the paper

“This suggests that heme might also trigger necroptosis [217].”

What the sources say

• Not checked yetcites [217] Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11: 700–714 source

In the paper

“Briefly, labile heme sensitizes parenchyma cells to undergo programmed cell death in response to proinflammatory cytokines such as TNF [106] as well as other agonists such as Fas as well as ROS and RNS [38,190].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“Free heme can also engage other PRR, as illustrated for NALP3 [206].”

What the sources say

• Not checked yetcites [206] Dutra FF, Alves LS, Rodrigues D, Fernandez PL, de Oliveira RB, Golenbock DT, Zamboni DS, Bozza MT (2014) Hemolysis‐induced lethality involves inflammasome activation by heme. Proc Natl Acad Sci USA 111: E4110–E4118 source

In the paper

“The mechanisms underlying the pathogenic effects of labile heme are probably diverse, but there is a growing body of evidence to suggest that labile heme acts as a pro-inflammatory agonist through the engagement of 204] and endothelial cells [205] (Fig 4).”

What the sources say

• Not checked yetcites [204] Figueiredo RT, Fernandez PL, Mourao‐Sa DS, Porto BN, Dutra FF, Alves LS, Oliveira MF, Oliveira PL, Graça‐Souza AV, Bozza MT (2007) Characterization of heme as activator of Toll‐like receptor 4. J Biol Chem 282: 20221–20229 source
• Not checked yetcites [205] Belcher JD, Chen C, Nguyen J, Milbauer L, Abdulla F, Alayash AI, Smith A, Nath KA, Hebbel RP, Vercellotti GM (2014) Heme triggers TLR4 signaling leading to endothelial cell activation and vaso‐occlusion in murine sickle cell disease. Blood 123: 377–390 source

In the paper

“The mechanism underlying heme-mediated cytotoxicity involves the sustained activation of the c-Jun N-terminal kinase (JNK) signaling transduction pathway [107] (Fig 4).”

What the sources say

• Not checked yetcites [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

In the paper

“Presumably, this occurs via a mechanism driven via the Fenton reaction in which hydrogen peroxide (H 2 O 2 ) oxidizes Fe 2+ , either within the context of the tetrapyrrole ring or when Fe is released from heme, to produce highly reactive hydroxyl radicals (OH .) [38,212].”

What the sources say

• Not checked yetcites [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 yetcites [212] Fenton HJH (1894) Oxidation of tartaric acid in presence of iron. J Chem Soc (Lond) 65: 899–910 source

In the paper

“The clinical relevance of this pathologic process is strongly supported by the recent finding that heme accumulation in plasma is associated with the development of severe forms of malaria in humans [202].”

What the sources say

• Not checked yetcites [202] Dalko E, Das B, Herbert F, Fesel C, Pathak S, Tripathy R, Cazenave PA, Ravindran B, Sharma S, Pied S (2015) Multifaceted roles of heme during severe Plasmodium falciparum infections in India. Infect Immun 83: 3793–3799 source

In the paper

“Labile heme also exerts chemotactic effects via the activation of G protein-coupled receptors expressed in PMN cells [207], while promoting the release of neutrophil extracellular traps (NETs) from activated PMN cells [208] (Fig 4).”

What the sources say

• Not checked yetcites [207] Porto BN, Alves LS, Fernandez PL, Dutra TP, Figueiredo RT, Graca‐Souza AV, Bozza MT (2007) Heme induces neutrophil migration and reactive oxygen species generation through signaling pathways characteristic of chemotactic receptors. J Biol Chem 282: 24430–24436 source

In the paper

“Once released from hemoglobin, the redox activity of labile heme becomes pro-oxidant and cytotoxic [38,106,107,190] (Fig 4).”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“Labile heme also exerts chemotactic effects via the activation of G protein-coupled receptors expressed in PMN cells [207], while promoting the release of neutrophil extracellular traps (NETs) from activated PMN cells [208] (Fig 4).”

What the sources say

• Not checked yetcites [208] Chen G, Zhang D, Fuchs TA, Manwani D, Wagner DD, Frenette PS (2014) Heme‐induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease. Blood 123: 3818–3827 source

In the paper

“Given the central role played these PRR in the activation of innate immunity, labile heme is likely to tailor resistance to infections associated with more or less severe hemolysis.”

In the paper

“Finally, approaches which block microbial Fe acquisition pathways, including binding of host Fe proteins, may prove to be effective in limiting microbial proliferation and pathogenicity as shown for Aspergillus spp.[33].”

What the sources say

• Not checked yetcites [33] Schrettl M, Bignell E, Kragl C, Joechl C, Rogers T, Arst HN Jr, Haynes K, Haas H (2004) Siderophore biosynthesis but not reductive iron assimilation is essential for Aspergillus fumigatus virulence. J Exp Med 200: 1213–1219 source

In the paper

“This was demonstrated, as a proof of principle, using Nifedipine, a calcium channel blocker that promotes Fe efflux from Mø and enhances host resistance to Salmonella infection in mice [233].”

What the sources say

• Not checked yetcites [233] Mair SM, Nairz M, Bellmann‐Weiler R, Muehlbacher T, Schroll A, Theurl I, Moser PL, Talasz H, Fang FC, Weiss G (2011) Nifedipine affects the course of Salmonella enterica serovar Typhimurium infection by modulating macrophage iron homeostasis. J Infect Dis 204: 685–694 source

In the paper

“In mucormycosis, an invasive mold infection, desferrioxamine shows adverse outcomes because mucorales can use desferrioxamine as a Fe source [237].”

What the sources say

• Not checked yetcites [237] Boelaert JR, de Locht M, Van Cutsem J, Kerrels V, Cantinieaux B, Verdonck A, Van Landuyt HW, Schneider YJ (1993) Mucormycosis during deferoxamine therapy is a siderophore‐mediated infection. In vitro and in vivo animal studies. J Clin Invest 91: 1979–1986 source

In the paper

“Moreover, CO acts per se as a cytoprotective molecule [172,228], which should also contribute to promote tissue damage control and disease tolerance to malaria.”

What the sources say

• Not checked yetcites [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 yetcites [228] Brouard S, Berberat PO, Tobiasch E, Seldon MP, Bach FH, Soares MP (2002) Heme oxygenase‐1‐derived carbon monoxide requires the activation of transcription factor NF‐kappa B to protect endothelial cells from tumor necrosis factor‐alpha‐mediated apoptosis. J Biol Chem 277: 17950–17961 source

In the paper

“However, a small, multicenter clinical study using desferasirox as an adjunct treatment in patients that develop mucormycosis after allogeneic bone marrow transplantation resulted in a rather unfavorable outcome, for reasons that are not clear [28].”

What the sources say

• Not checked yetcites [28] Spellberg B, Ibrahim AS, Chin‐Hong PV, Kontoyiannis DP, Morris MI, Perfect JR, Fredricks D, Brass EP (2012) The Deferasirox‐AmBisome Therapy for Mucormycosis (DEFEAT Mucor) study: a randomized, double‐blinded, placebo‐controlled trial. J Antimicrob Chemother 67: 715–722 source

In the paper

“This immunoregulatory effect is reinforced by IL-10, which acts as a positive feedback loop to induce further HO-1 expression and CO production [116].”

What the sources say

• Not checked yetcites [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

In the paper

“Production of CO by HO-1 targets the extracellular hemoglobin generated during the blood stage of Plasmodium infection and prevents the pathogenesis of severe forms of malaria [103][104][105].”

What the sources say

• Not checked yetcites [103][104][105]

In the paper

“This suggests that CO regulates Mø polarization, in a manner that should limit the extent of tissue damage associated with Mø activation, in the context of infectious diseases, such as sepsis driven by polymicrobial infection [190] as well as severe forms of malaria [103-106], tuberculosis [47,170,226], or trypanosomiasis [227].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [47] Andrade BB, Pavan Kumar N, Mayer‐Barber KD, Barber DL, Sridhar R, Rekha VV, Jawahar MS, Nutman TB, Sher A, Babu S (2013) Plasma heme oxygenase‐1 levels distinguish latent or successfully treated human tuberculosis from active disease. PLoS ONE 8: e62618 source
• Not checked yetcites [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 yetcites [226] Isanaka S, Aboud S, Mugusi F, Bosch RJ, Willett WC, Spiegelman D, Duggan C, Fawzi WW (2012) Iron status predicts treatment failure and mortality in tuberculosis patients: a prospective cohort study from Dar es Salaam, Tanzania. PLoS ONE 7: e37350 source

In the paper

“The gasotransmitter CO, produced via heme catabolism by HO-1, also confers disease tolerance to systemic infections, as demonstrated for malaria [105].”

What the sources say

• Not checked yetcites [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

In the paper

“Considering that physiologic mechanisms promoting Fe efflux from Mø confer resistance to intracellular bacteria [73,98,99,157], drugs that promote this process should enhance resistance to intracellular bacteria.”

In the paper

“Considering that physiologic mechanisms promoting Fe efflux from Mø confer resistance to intracellular bacteria [73,98,99,157], drugs that promote this process should enhance resistance to intracellular bacteria.”

What the sources say

• Not checked yetcites [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 yetcites [98] Chlosta S, Fishman DS, Harrington L, Johnson EE, Knutson MD, Wessling‐Resnick M, Cherayil BJ (2006) The iron efflux protein ferroportin regulates the intracellular growth of Salmonella enterica. Infect Immun 74: 3065–3067 source
• Not checked yetcites [99] Paradkar PN, De Domenico I, Durchfort N, Zohn I, Kaplan J, Ward DM (2008) Iron depletion limits intracellular bacterial growth in macrophages. Blood 112: 866–874 source
• Not checked yetcites [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

In the paper

“In contrast, infection by extracellular pathogens should be better controlled by pharmacologic agents that reduce Mø efflux and decrease the levels of circulating Fe, such as hepcidin or hepcidin mimetics [95].”

What the sources say

• Not checked yetcites [95] Ganz T (2009) Iron in innate immunity: starve the invaders. Curr Opin Immunol 21: 63–67 source

In the paper

“While reputedly toxic when targeting hemoglobin in RBC, binding of CO to extracellular hemoglobin inhibits hemoglobin oxidation and the release of its prosthetic heme groups [103][104][105]199], thus preventing labile heme from partaking in the pathogenesis of severe forms of malaria [103][104][105].”

What the sources say

• Not checked yetcites [103][104][105]199]
• Not checked yetcites [103][104][105]

In the paper

“This salutary effect relies essentially on the intrinsic ability of CO to bind Fe 2+ in the heme groups of hemoglobin [103][104][105]199].”

What the sources say

• Not checked yetcites [103][104][105]199]

In the paper

“In the context of systemic infections, the protective effects exerted by HO-1 are assisted by FTH [54,107] (Fig 4).”

What the sources say

• Not checked yetcites [54] Gozzelino R, Soares MP (2014) Coupling heme and iron metabolism via ferritin H chain. Antioxid Redox Signal 20: 1754–1769 source
• Not checked yetcites [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

In the paper

“It is likely that a similar mechanism underlies the protective effect exerted by other chronic hemolytic conditions against malaria, including hemoglobin C [229,230], glucose 6 phosphate dihydrogenase (G6PD) deficiency in males [231], bor a-thalassemia [230] as well as mutations involved in RBC cytoskeleton or membrane protein defects [232].”

What the sources say

• Not checked yetcites [229] Modiano D, Luoni G, Sirima BS, Simporé J, Verra F, Konaté A, Rastrelli E, Olivieri A, Calissano C, Paganotti GM et al (2001) Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature 414: 305–308 source
• Not checked yetcites [230] May J, Evans JA, Timmann C, Ehmen C, Busch W, Thye T, Agbenyega T, Horstmann RD (2007) Hemoglobin variants and disease manifestations in severe falciparum malaria. JAMA 297: 2220–2226 source
• Not checked yetcites [231] Guindo A, Fairhurst RM, Doumbo OK, Wellems TE, Diallo DA (2007) X‐linked G6PD deficiency protects hemizygous males but not heterozygous females against severe malaria. PLoS Med 4: e66 source
• Not checked yetcites [232] Williams TN (2006) Human red blood cell polymorphisms and malaria. Curr Opin Microbiol 9: 388–394 source

In the paper

“Perhaps the strongest argument in support of this strategy is provided by anti-malarial drugs, which target in most cases Plasmodium heme metabolism [239].”

What the sources say

• Not checked yetcites [239] Sigala PA, Goldberg DE (2014) The peculiarities and paradoxes of Plasmodium heme metabolism. Annu Rev Microbiol 68: 259–278 source

In the paper

“Delivery of Lcn2 by probiotic bacteria has also been shown to control Salmonella infection [235].”

What the sources say

• Not checked yetcites [235] Deriu E, Liu JZ, Pezeshki M, Edwards RA, Ochoa RJ, Contreras H, Libby SJ, Fang FC, Raffatellu M (2013) Probiotic bacteria reduce salmonella typhimurium intestinal colonization by competing for iron. Cell Host Microbe 14: 26–37 source

In the paper

“There are other examples, indicating a beneficial effect of targeting Fe, as illustrated for the ability of lactoferrin to prevent bacterial biofilm formation [122].”

What the sources say

• Not checked yetcites [122] Singh PK, Parsek MR, Greenberg EP, Welsh MJ (2002) A component of innate immunity prevents bacterial biofilm development. Nature 417: 552–555 source

In the paper

“The finding that sickle hemizygous mutations confer protection against malaria via a CO-dependent mechanism supports its pathophysiological relevance [103][104][105].”

What the sources say

• Not checked yetcites [103][104][105]

In the paper

“The NO produced by iNOS/NOS2 induces, via Keap1, the activation of the transcription factor Nrf2, which induces the expression of FPN and hence Fe export from phagolysosomes and/or from the cytoplasm.”

In the paper

“More than 80% of the bioavailable Fe in mammals exists in the form of heme contained in hemoproteins[241].”

What the sources say

• Not checked yetcites [241] Fischer H, Zeile K (1929) Synthese des haematoporphyrins, protoporphyrins und haemins. Justus Liebigs Annalen der Chemie 468: 98–116 source

In the paper

“The recent finding that HO-1 is central to support resistance to Mycobacteria infection in mice suggests that targeting heme catabolism may be used therapeutically against tuberculosis [170].”

What the sources say

• Not checked yetcites [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

In the paper

“The recent finding that HO-1 is central to support resistance to Mycobacteria infection in mice suggests that targeting heme catabolism may be used therapeutically against tuberculosis [170].”

What the sources say

• Not checked yetcites [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

In the paper

“CO also binds to the heme groups of extracellular hemoglobin and prevents heme release, thus protecting tissues from the vasoactive, pro-inflammatory, and cytotoxic effects of labile heme.”

In the paper

“Heme catabolism by HO-1 induces the expression of the Fe-scavenging protein ferritin that stores intracellular Fe in Mø, away from intracellular pathogens.”

In the paper

“Fe or heme is exported from phagolysosomes by NRAMP1 and FPN or by HRG1, reducing Fe and heme availability to pathogens residing within this subcellular compartment.”

In the paper

“The hemoglobin and heme scavengers HP and HPX, respectively, shuttle heme for degradation by HO-1 via the Mø scavenger receptors CD163 and CD91 (middle).”

In the paper

“Pharmacologic induction of HO-1 has also been used experimentally to modulate resistance or tolerance to bacterial or protozoan infections in mice [220].”

What the sources say

• Not checked yetcites [220] Soares MP, Bach FH (2009) Heme oxygenase‐1: from biology to therapeutic potential. Trends Mol Med 15: 50–58 source

In the paper

“The most abundant pool of Fe in mammals are the prosthetic heme groups of hemoglobin in red blood cells (RBC), followed by the heme groups of myoglobin in muscle cells and those of cytochromes and other ubiquitously expressed hemoproteins in all cells[38,54].”

What the sources say

• Not checked yetcites [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 yetcites [54] Gozzelino R, Soares MP (2014) Coupling heme and iron metabolism via ferritin H chain. Antioxid Redox Signal 20: 1754–1769 source

In the paper

“Upon infection by extracellular pathogens, Mø can uptake extracellular Fe via different mechanisms involving Tf/TfR interaction, (D) the lactoferrin/lactoferrin receptor, (E) the Lcn2/Lcn2R, or (F) the divalent metal transporter DMT1.”

In the paper

“Mø activation in response to intracellular pathogens is associated with a reduction of intracellular Fe levels.”

In the paper

“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.”

In the paper

“In addition, cytokines, such as IFNc and TNF, also inhibit FPN transcription in Mø (not shown) promoting Fe retention and limiting further Fe availability to extracellular microbes.”

In the paper

“Mø activation in response to PRR and/or IFNcR signaling activates the transcription factors NF-jB and STAT1/2, which induce the expression of the Fe-binding proteins ferritin, lactoferrin, Lcn2, and the Fe transporter DMT1 as well as NOX2/gp91 phox and iNOS/NOS2.”