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Cited by 155Antimicrobial Resistance in StaphylococcusBacterial Genetics and BiotechnologyBacterial biofilms and quorum sensing

Metal ion acquisition in Staphylococcus aureus: overcoming nutritional immunity

Open access
Cassat, James E., Skaar, Eric P.·2012·Seminars in Immunopathology
DOI 10.1007/s00281-011-0294-4PMC PMC3796439
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Abstract

Transition metals are essential nutrients to virtually all forms of life, including bacterial pathogens. In Staphylococcus aureus, metal ions participate in diverse biochemical processes such as metabolism, DNA synthesis, regulation of virulence factors, and defense against oxidative stress. As an innate immune response to bacterial infection, vertebrate hosts sequester transition metals in a process that has been termed "nutritional immunity." To successfully infect vertebrates, S. aureus must overcome host sequestration of these critical nutrients. The objective of this review is to outline the current knowledge of staphylococcal metal ion acquisition systems, as well as to define the host mechanisms of nutritional immunity during staphylococcal infection.

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  • Premisecitation

    Iron sequestration is the best-characterized example of nutritional immunity during staphylococcal infection, with iron kept intracellularly or bound to high-affinity host proteins.

    “The most well characterized example of nutritional immunity during staphylococcal infection is iron sequestration, in which iron is maintained predominantly intracellularly or in complex with high-affinity host binding proteins [32].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Weinberg ED (2009) Iron availability and infection. Biochim Biophys Acta 1790(7):600–605. doi:10.1016/j.bbagen.2008.07.002 source

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  • Premisecitation

    Emerging evidence indicates that nutritional immunity extends to other transition metals, including zinc and manganese.

    “Emerging evidence suggests that the principle of nutritional immunity extends to other transition metals, including zinc and manganese [34].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Corbin BD, Seeley EH, Raab A, Feldmann J, Miller MR, Torres VJ, Anderson KL, Dattilo BM, Dunman PM, Gerads R, Caprioli RM, Nacken W, Chazin WJ, Skaar EP (2008) Metal chelation and inhibition of bacterial growth in tissue abscesses. Science 319(5865):962–965. doi:10.1126/science.1152449 source

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  • Interpretationreasoning

    Because iron is required for bacterial proliferation, S. aureus must circumvent iron sequestration to successfully infect host tissues.

    “Since iron is necessary for bacterial proliferation, S. aureus must circumvent iron sequestration in order to successfully infect host tissues.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Iron is necessary for bacterial proliferation.
  • Premisecitation

    Iron sequestration results in extracellular iron concentration too low to support bacterial growth.

    “The result of this sequestration is an extracellular iron concentration insufficient to support bacterial growth [33].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Braun V, Hantke K, Koster W (1998) Bacterial iron transport: mechanisms, genetics, and regulation. Met Ions Biol Syst 35:67–145

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  • Interpretationreasoning

    Staphylococci have evolved systems to acquire, process, and detoxify iron and iron-containing host molecules and proteins.

    “Accordingly, staphylococci have evolved systems for the acquisition, processing, and detoxification of iron and iron-containing host molecules and proteins.”
    Quote in the paperSubstantial claim
  • May combine two claims. 53
  • Classified as probably not a substantial claim. 20

  • May combine two claims.

    Interpretationreasoning

    Most vertebrate iron is intracellular, stored in ferritin or complexed to heme, making it inaccessible to predominantly extracellular pathogens such as S. aureus.

    “The majority of vertebrate iron is therefore inaccessible to predominantly extracellular pathogens such as S. aureus.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: S. aureus is predominantly an extracellular pathogen.

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    Premisecitation

    In response to infection, mammalian hosts further limit iron availability by decreasing dietary iron absorption, reducing macrophage iron release, and releasing apolactoferrin from neutrophil granules.

    “In response to infection, mammalian hosts can further limit iron availability through a number of mechanisms including decreased dietary iron absorption, reduced release of iron from macrophages, and release of apolactoferrin from neutrophil granules at the site of infection [32].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Weinberg ED (2009) Iron availability and infection. Biochim Biophys Acta 1790(7):600–605. doi:10.1016/j.bbagen.2008.07.002 source

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  • Classified as probably not a substantial claim.

    Premisecitation

    Nutritional immunity is the host process of sequestering nutrients essential for bacterial growth, thereby limiting pathogen proliferation.

    “Nutritional immunity describes the process whereby a host sequesters nutrients essential to bacterial growth, thus limiting the ability of invading pathogens to proliferate in the host environment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Kochan I (1973) The role of iron in bacterial infections, with special consideration of host-tubercle bacillus interaction. Curr Top Microbiol Immunol 60:1–30 source

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  • May combine two claims.

    Premisecitation

    Staphyloferrin A is a 479 Da molecule encoded by the sfaABCD gene cluster, and its iron complex is transported across the membrane by ABC transporter HtsABC powered by ATPase FhuC.

    “Staphyloferrin A is a 479 Da molecule encoded by the sfaABCD gene cluster [47, 52]. Following iron complexation by staphyloferrin A, transport across the staphylococcal membrane is mediated by the ABC transporter HtsABC, in a process powered by a separate ATPase, FhuC (Fig. 1) [47, 53].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [47] Beasley FC, Vines ED, Grigg JC, Zheng Q, Liu S, Lajoie GA, Murphy ME, Heinrichs DE (2009) Characterization of staphyloferrin A biosynthetic and transport mutants in Staphylococcus aureus. Mol Microbiol 72(4):947–963. doi:10.1111/j.1365-2958.2009.06698.x source

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    • cites [52] Cotton JL, Tao J, Balibar CJ (2009) Identification and characterization of the Staphylococcus aureus gene cluster coding for staphyloferrin A. Biochemistry 48(5):1025–1035. doi:10.1021/bi801844c source

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    • cites [53] Speziali CD, Dale SE, Henderson JA, Vines ED, Heinrichs DE (2006) Requirement of Staphylococcus aureus ATP-binding cassette-ATPase FhuC for iron-restricted growth and evidence that it functions with more than one iron transporter. J Bacteriol 188(6):2048–2055. doi:10.1128/JB.188.6.2048-2055.2006 source

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    Premisecitation

    In iron-replete conditions, Fur binds Fur boxes upstream of Fur-regulated genes and represses transcription; in iron-deplete conditions, Fur does not bind and transcription proceeds.

    “In iron-replete conditions, Fur binds a consensus DNA sequence (Fur box) upstream of Fur-regulated genes, leading to transcriptional repression. In iron-deplete conditions, Fur no longer binds to Fur boxes, and transcription of Fur-regulated genes can proceed.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Xiong A, Singh VK, Cabrera G, Jayaswal RK (2000) Molecular characterization of the ferric-uptake regulator, Fur, from Staphylococcus aureus. Microbiology 146(Pt 3):659–668 source

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

    Premisecitation

    Fur is an iron-dependent transcriptional regulator conserved among Gram-positive and Gram-negative bacteria.

    “Fur is an iron-dependent transcriptional regulator that is conserved among Gram-positive and Gram-negative bacteria [50].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Hantke K (1981) Regulation of ferric iron transport in Escherichia coli K12: isolation of a constitutive mutant. Mol Gen Genet 182(2):288–292 source

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  • May combine two claims.

    Premisecitation

    Staphyloferrin B is a 448 Da compound composed of L-2,3-diaminopropionic acid, 1,2-diaminoethane, and α-ketoglutaric acid, produced by the sbnABCDEFGHI operon and transported by SirABC.

    “Staphyloferrin B is a 448 Da compound composed of L-2,3-diaminopropionic acid, 1,2-diaminoethane, and α-ketoglutaric acid [56]. Staphyloferrin B is a product of the sbnABCDEFGHI operon, of which only SbnC, SbnE, SbnF, and SbnH are required for in vitro synthesis [57]. Transport of staphyloferrin B across the staphylococcal cell membrane is mediated by the staphylococcal iron-regulated transporter”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [56] Drechsel H, Freund S, Nicholson G, Haag H, Jung O, Zahner H, Jung G (1993) Purification and chemical characterization of staphyloferrin B, a hydrophilic siderophore from staphylococci. Biometals 6(3):185–192 source

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    • cites [57] Cheung J, Beasley FC, Liu S, Lajoie GA, Heinrichs DE (2009) Molecular characterization of staphyloferrin B biosynthesis in Staphylococcus aureus. Mol Microbiol 74(3):594–608. doi:10.1111/j.1365-2958.2009.06880.x source

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    • cites [58] Dale SE, Sebulsky MT, Heinrichs DE (2004) Involvement of SirABC in iron-siderophore import in Staphylococcus aureus. J Bacteriol 186(24):8356–8362. doi:10.1128/JB.186.24.8356-8362.2004 source

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    • cites [59] Grigg JC, Cheung J, Heinrichs DE, Murphy ME (2010) Specificity of Staphyloferrin B recognition by the SirA receptor from Staphylococcus aureus. J Biol Chem 285(45):34579–34588. doi:10.1074/jbc.M110.172924 source

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  • May combine two claims.

    Premisecitation

    Individuals with iron overload have increased susceptibility to bacterial infection; patients with hemochromatosis are more susceptible to Yersinia enterocolitica, Vibrio vulnificans, and Listeria monocytogenes.

    “For example, patients with hemochromatosis are more susceptible to infection by Yersinia enterocolitica, Vibrio vulnificans, and Listeria monocytogenes [39–42].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [39] Vadillo M, Corbella X, Pac V, Fernandez-Viladrich P, Pujol R (1994) Multiple liver abscesses due to Yersinia enterocolitica discloses primary hemochromatosis: three cases reports and review. Clin Infect Dis 18(6):938–941 source

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    • cites [40] Barton JC, Acton RT (2009) Hemochromatosis and Vibrio vulnificus wound infections. J Clin Gastroenterol 43(9):890–893. doi:10.1097/MCG.0b013e31819069c1 source

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    • cites [41] Weinberg ED (2000) Microbial pathogens with impaired ability to acquire host iron. Biometals 13(1):85–89 source

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    • cites [42] Manso C, Rivas I, Peraire J, Vidal F, Richart C (1997) Fatal Listeria meningitis, endocarditis and pericarditis in a patient with haemochromatosis. Scand J Infect Dis 29(3):308–309 source

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  • May combine two claims.

    Premisecitation

    Mutation of FhuC decreases murine morbidity but not colony recovery in a kidney abscess model.

    “Mutation of the gene encoding FhuC, the ABC-type ATPase required for both staphyloferrin A and B uptake, results in decreased murine morbidity, but not colony recovery, in a kidney abscess model [53].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Speziali CD, Dale SE, Henderson JA, Vines ED, Heinrichs DE (2006) Requirement of Staphylococcus aureus ATP-binding cassette-ATPase FhuC for iron-restricted growth and evidence that it functions with more than one iron transporter. J Bacteriol 188(6):2048–2055. doi:10.1128/JB.188.6.2048-2055.2006 source

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

    Premisecitation

    Mutation of sbnE significantly decreases colony recovery in a murine kidney abscess model.

    “This result is in contrast to previously published data in which mutation of sbnE significantly decreased colony recovery in a murine kidney abscess model [74].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Dale SE, Doherty-Kirby A, Lajoie G, Heinrichs DE (2004) Role of siderophore biosynthesis in virulence of Staphylococcus aureus: identification and characterization of genes involved in production of a siderophore. Infect Immun 72(1):29–37 source

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  • May combine two claims.

    Premisecitation

    In vertebrates, heme is the primary iron reservoir, representing up to 80% of total body iron, while transferrin-bound iron is less than 1%.

    “In vertebrates, heme is the primary reservoir of iron, representing up to 80% of total body iron. This is in contrast to transferrin-bound iron, which represents less than 1% of total body iron [38].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Crichton R (2001) Inorganic biochemistry of iron metabolism: from molecular mechanisms to clinical consequences, vol 2. Wiley, West Sussex source

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

    Interpretationnone given

    Stealth siderophores have not been described in S. aureus.

    “Stealth side-rophores have not been described in S. aureus.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Hemoglobin released from erythrocytes is bound by haptoglobin and processed by the reticuloendothelial system, and free heme in plasma can be sequestered by albumin, hemopexin, and alpha-1-microglobulin.

    “Hemoglobin liberated from erythrocytes is bound by the high-affinity binding protein haptoglobin and subsequently processed by the reticuloendothelial system [88]. Additionally, free heme released into plasma can be sequestered by albumin, hemopexin, and alpha-1-microglobulin [86, 88, 89].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [86] Young NS, Gerson SL, High KA (2006) Clinical hematology, vol 1. Mosby Elsevier, Philadelphia

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    • cites [88] Kristiansen M, Graversen JH, Jacobsen C, Sonne O, Hoffman HJ, Law SK, Moestrup SK (2001) Identification of the haemoglobin scavenger receptor. Nature 409(6817):198–201. doi:10.1038/35051594 source

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    • cites [89] Allhorn M, Berggard T, Nordberg J, Olsson ML, Akerstrom B (2002) Processing of the lipocalin alpha(1)-microglobulin by hemoglobin induces heme-binding and heme-degradation properties. Blood 99(6):1894–1901 source

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  • May combine two claims.

    Premisecitation

    Inactivation of either the catecholamine transporter Sst alone, both siderophore operons sfa and sbn, or both siderophore transporters Hts and Sir reduces colony recovery from hearts of systemically infected mice.

    “Inactivation of either the catecholamine transporter (Sst) alone, both siderophore operons (sfa and sbn), or both siderophore transporters (Hts and Sir) yields a reduction in colony recovery from the hearts of systemically infected mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Beasley FC, Marolda CL, Cheung J, Buac S, Heinrichs DE (2011) Staphylococcus aureus transporters Hts, Sir, and Sst capture iron liberated from human transferrin by staphyloferrin a, staphyloferrin B, and catecholamine stress hormones, respectively, and contribute to virulence. Infect Immun 79(6):2345–2355. doi:10.1128/IAI.00117-11 source

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  • May combine two claims.

    Premisecitation

    Combined inactivation of sfa, sbn, and sst reduces colony recovery from heart and liver, while combined inactivation of sst, sirA, and hts decreases colony recovery in heart, liver, and kidney.

    “Additionally, combined inactivation of sfa, sbn, and sst results in reduced colony recovery from the heart and liver, whereas combined inactivation of sst, sirA, and hts decreases colony recovery in heart, liver, and kidney.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Beasley FC, Marolda CL, Cheung J, Buac S, Heinrichs DE (2011) Staphylococcus aureus transporters Hts, Sir, and Sst capture iron liberated from human transferrin by staphyloferrin a, staphyloferrin B, and catecholamine stress hormones, respectively, and contribute to virulence. Infect Immun 79(6):2345–2355. doi:10.1128/IAI.00117-11 source

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  • May combine two claims.

    Interpretationcitation

    Although siderophore-mediated iron acquisition promotes staphylococcal growth in iron-limited conditions in vitro and in vivo, the preferred iron source for S. aureus is heme.

    “Although siderophore-mediated iron acquisition promotes staphylococcal growth in iron-limited conditions in vitro and in vivo, the preferred iron source for S. aureus is heme.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    IsdG and IsdI degrade heme to iron and a novel chromophore, staphylobilin, unlike human heme-oxygenases which produce biliverdin.

    “Unlike human heme-oxygenases which degrade heme to iron and the chromophore biliverdin, IsdG and IsdI degrade heme to iron and a novel chromophore, staphylobilin [104].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [104] Reniere ML, Ukpabi GN, Harry SR, Stec DF, Krull R, Wright DW, Bachmann BO, Murphy ME, Skaar EP (2010) The IsdG-family of haem oxygenases degrades haem to a novel chromophore. Mol Microbiol 75(6):1529–1538. doi:10.1111/j.1365-2958.2010.07076.x source

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  • May combine two claims.

    Premisecitation

    Mutation of isdDEF decreases but does not abolish S. aureus growth on heme, suggesting IsdDEF-independent mechanisms of heme import.

    “Interestingly, mutation of isdDEF decreases, but does not abolish, the ability of S. aureus to grow on heme, suggesting that there are IsdDEF-independent mechanisms of heme import [101].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [101] Mazmanian SK, Skaar EP, Gaspar AH, Humayun M, Gornicki P, Jelenska J, Joachmiak A, Missiakas DM, Schneewind O (2003) Passage of heme-iron across the envelope of Staphylococcus aureus. Science 299(5608):906–909. doi:10.1126/science.1081147 source

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    Premisecitation

    Deletion of either isdG or isdI decreases the ability to utilize heme, indicating the enzymes are not functionally redundant.

    “Deletion of either isdG or isdI results in a decreased ability to utilize heme, indicating that these enzymes are not functionally redundant [105].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Reniere ML, Skaar EP (2008) Staphylococcus aureus haem oxygenases are differentially regulated by iron and haem. Mol Microbiol 69(5):1304–1315. doi:10.1111/j.1365-2958.2008.06363.x source

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  • May combine two claims.

    Premisecitation

    Both isdG and isdI are transcriptionally regulated by iron, with maximal expression in iron-limited conditions, and IsdG is post-transcriptionally regulated by heme.

    “Both isdG and isdI are transcriptionally regulated by iron, such that maximal expression occurs in iron-limited conditions. IsdG is also post-transcriptionally regulated by heme, as protein stability is enhanced in the presence of heme [105].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Reniere ML, Skaar EP (2008) Staphylococcus aureus haem oxygenases are differentially regulated by iron and haem. Mol Microbiol 69(5):1304–1315. doi:10.1111/j.1365-2958.2008.06363.x source

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  • May combine two claims.

    Interpretationreasoning

    These mechanisms protect the host from heme toxicity while limiting heme and hemoprotein availability to invading pathogens.

    “These mechanisms protect the host from heme toxicity, while also limiting the availability of heme and hemoproteins to invading pathogens.”
    Quote in the paperSubstantial claim

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    Premisecitation

    The two-component system upstream of hrtAB, named HssR and HssS, is required for the adaptive response to heme toxicity and activates transcription of hrtAB.

    “The two-component system upstream of hrtAB, subsequently named the heme sensor system (HssR and HssS), is required for the adaptive response to heme toxicity and activates transcription of hrtAB [106].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [106] Torres VJ, Stauff DL, Pishchany G, Bezbradica JS, Gordy LE, Iturregui J, Anderson KL, Dunman PM, Joyce S, Skaar EP (2007) A Staphylococcus aureus regulatory system that responds to host heme and modulates virulence. Cell Host Microbe 1(2):109–119. doi:10.1016/j.chom.2007.03.001 source

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    Premisecitation

    Passive immunization with anti-Hla antibodies or active immunization with nontoxigenic Hla is protective in animal models of staphylococcal infection.

    “Moreover, passive immunization with anti-Hla antibodies or active immunization with nontoxigenic Hla is protective in animal models of staphylococcal infection [108, 115].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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  • May combine two claims.

    Interpretationcitation

    S. aureus senses heme through HssRS, increasing transcription of hrtAB, which alleviates heme toxicity.

    “Thus, S. aureus senses heme through HssRS, increasing transcription of hrtAB, which leads to alleviation of heme toxicity.”
    Quote in the paperSubstantial claim

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    Premisecitation

    IsdA and IsdB were identified as vaccine candidates using reverse vaccinology, and immunization with these proteins is protective in murine models of infection.

    “IsdA and IsdB were identified as vaccine candidates using “reverse vaccinology” [119], and subsequent studies confirmed that immunization with these proteins is protective in murine models of infection [117, 120–123].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [119] Maione D, Margarit I, Rinaudo CD, Masignani V, Mora M, Scarselli M, Tettelin H, Brettoni C, Iacobini ET, Rosini R, D’Agostino N, Miorin L, Buccato S, Mariani M, Galli G, Nogarotto R, Nardi Dei V, Vegni F, Fraser C, Mancuso G, Teti G, Madoff LC, Paoletti LC, Rappuoli R, Kasper DL, Telford JL, Grandi G (2005) Identification of a universal group B streptococcus vaccine by multiple genome screen. Science 309(5731):148–150. doi:10.1126/science.1109869 source

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    • cites [117] Kim HK, DeDent A, Cheng AG, McAdow M, Bagnoli F, Missiakas DM, Schneewind O (2010) IsdA and IsdB antibodies protect mice against Staphylococcus aureus abscess formation and lethal challenge. Vaccine 28(38):6382–6392. doi:10.1016/j.vaccine.2010.02.097 source

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    • cites [120] Stranger-Jones YK, Bae T, Schneewind O (2006) Vaccine assembly from surface proteins of Staphylococcus aureus. Proc Natl Acad Sci U S A 103(45):16942–16947. doi:10.1073/pnas.0606863103 source

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    • cites [122] Clarke SR, Brummell KJ, Horsburgh MJ, McDowell PW, Mohamad SA, Stapleton MR, Acevedo J, Read RC, Day NP, Peacock SJ, Mond JJ, Kokai-Kun JF, Foster SJ (2006) Identification of in vivo-expressed antigens of Staphylococcus aureus and their use in vaccinations for protection against nasal carriage. J Infect Dis 193(8):1098–1108. doi:10.1086/501471 source

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    • cites [123] Ebert T, Smith S, Pancari G, Clark D, Hampton R, Secore S, Towne V, Fan H, Wang XM, Wu X, Ernst R, Harvey BR, Finnefrock AC, Wang F, Tan C, Durr E, Cope L, Anderson A, An Z, McNeely T (2010) A fully human monoclonal antibody to Staphylococcus aureus iron regulated surface determinant B (IsdB) with functional activity in vitro and in vivo. Hum Antibodies 19(4):113–128. doi:10.3233/HAB-2010-0235 source

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  • May combine two claims.

    Premisecitation

    IsdA binds fibrinogen and fibronectin in vitro, indicating a potential role as an iron-regulated adhesin.

    “IsdA binds both fibrinogen and fibronectin in vitro, indicating a potential role as an iron-regulated adhesin [125].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Clarke SR, Wiltshire MD, Foster SJ (2004) IsdA of Staphylococcus aureus is a broad spectrum, iron-regulated adhesin. Mol Microbiol 51(5):1509–1519. doi:10.1111/j.1365-2958.2003.03938.x source

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    Premisecitation

    Mice expressing human hemoglobin are more susceptible to S. aureus infection, with increased colony recovery from infected organs.

    “Compared to wild-type mice, mice expressing human hemoglobin are more susceptible to S. aureus infection, as evidenced by increased colony recovery from infected organs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [118] Pishchany G, McCoy AL, Torres VJ, Krause JC, Crowe JE Jr, Fabry ME, Skaar EP (2010) Specificity for human hemoglobin enhances Staphylococcus aureus infection. Cell Host Microbe 8(6):544–550. doi:10.1016/j.chom.2010.11.002 source

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    Premisecitation

    IsdA facilitates binding to human desquamated epithelial cells and promotes nasal colonization in rats.

    “Consistent with this hypothesis, IsdA facilitates binding to human desquamated epithelial cells, and promotes nasal colonization in rats [122, 126, 127].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [122] Clarke SR, Brummell KJ, Horsburgh MJ, McDowell PW, Mohamad SA, Stapleton MR, Acevedo J, Read RC, Day NP, Peacock SJ, Mond JJ, Kokai-Kun JF, Foster SJ (2006) Identification of in vivo-expressed antigens of Staphylococcus aureus and their use in vaccinations for protection against nasal carriage. J Infect Dis 193(8):1098–1108. doi:10.1086/501471 source

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    • cites [126] Corrigan RM, Miajlovic H, Foster TJ (2009) Surface proteins that promote adherence of Staphylococcus aureus to human desquamated nasal epithelial cells. BMC Microbiol 9:22. doi:10.1186/1471-2180-9-22 source

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    • cites [127] Clarke SR, Andre G, Walsh EJ, Dufrene YF, Foster TJ, Foster SJ (2009) Iron-regulated surface determinant protein A mediates adhesion of Staphylococcus aureus to human corneocyte envelope proteins. Infect Immun 77(6):2408–2416. doi:10.1128/IAI.01304-08 source

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  • May combine two claims.

    Premisecitation

    Mutation of isdA leads to increased susceptibility to hydrogen peroxide and killing by human neutrophils.

    “Mutation of isdA also leads to increased susceptibility to hydrogen peroxide and to killing by human neutrophils [129].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] Palazzolo-Ballance AM, Reniere ML, Braughton KR, Sturdevant DE, Otto M, Kreiswirth BN, Skaar EP, DeLeo FR (2008) Neutrophil microbicides induce a pathogen survival response in community-associated methicillin-resistant Staphylococcus aureus. J Immunol 180(1):500–509 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IsdA decreases staphylococcal cell hydrophobicity, increasing resistance to antimicrobial compounds in human sebum and other antimicrobial peptides.

    “By decreasing staphylococcal cell hydrophobicity, IsdA increases the resistance of S. aureus to antimicrobial compounds produced by human sebum, as well as other antimicrobial peptides [128].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [128] Clarke SR, Mohamed R, Bian L, Routh AF, Kokai-Kun JF, Mond JJ, Tarkowski A, Foster SJ (2007) The Staphylococcus aureus surface protein IsdA mediates resistance to innate defenses of human skin. Cell Host Microbe 1(3):199–212. doi:10.1016/j.chom.2007.04.005 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    IsdA also contributes to staphylococcal pathogenesis through roles in adhesion to host tissues and resistance to innate immune responses.

    “In addition to its role as a heme-binding protein, there is evidence that IsdA also contributes to staphylococcal pathogenesis through roles in both adhesion to host tissues and resistance to innate immune responses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Bacteria must acquire manganese and regulate its intracellular concentration.

    “Bacteria, like humans, must acquire manganese and regulate its intracellular concentration.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [136] Jakubovics NS, Jenkinson HF (2001) Out of the iron age: new insights into the critical role of manganese homeostasis in bacteria. Microbiology 147(Pt 7):1709–1718 source

      Not checked in the free run.

    • Rests on an assumption: Manganese is an essential nutrient for both eukaryotic and prokaryotic organisms.

  • May combine two claims.

    Premisecitation

    Upon entering the cytoplasm, heme is degraded by IsdG or IsdI to liberate iron, a process that contributes to staphylococcal virulence.

    “Upon entering the cytoplasm, heme is degraded by IsdG or IsdI to liberate iron, a process that also contributes to staphylococcal virulence.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Reniere ML, Skaar EP (2008) Staphylococcus aureus haem oxygenases are differentially regulated by iron and haem. Mol Microbiol 69(5):1304–1315. doi:10.1111/j.1365-2958.2008.06363.x source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inactivation of either htsB or htsC significantly reduces heme acquisition and decreases bacterial recovery and abscess formation in mice infected systemically with S. aureus.

    “Inactivation of either htsB or htsC significantly reduces heme acquisition and decreases bacterial recovery and abscess formation in mice infected systemically with S. aureus [54].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Skaar EP, Humayun M, Bae T, DeBord KL, Schneewind O (2004) Iron-source preference of Staphylococcus aureus infections. Science 305(5690):1626–1628. doi:10.1126/science.1099930 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutation of mntA in S. aureus reduces growth rate in metal-depleted minimal media, reversible by adding manganese.

    “Mutation of mntA in S. aureus results in a reduced growth rate in metal-depleted minimal media, a phenotype that is reversible upon addition of manganese.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [144] Horsburgh MJ, Wharton SJ, Cox AG, Ingham E, Peacock S, Foster SJ (2002) MntR modulates expression of the PerR regulon and superoxide resistance in Staphylococcus aureus through control of manganese uptake. Mol Microbiol 44(5):1269–1286 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The S. aureus genome encodes MntABC-type and Nramp-type manganese transporters, both functionally characterized.

    “The S. aureus genome encodes MntABC-type (mntABC) and Nramp-type (mntH) manganese transporters, both of which have been functionally characterized.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [144] Horsburgh MJ, Wharton SJ, Cox AG, Ingham E, Peacock S, Foster SJ (2002) MntR modulates expression of the PerR regulon and superoxide resistance in Staphylococcus aureus through control of manganese uptake. Mol Microbiol 44(5):1269–1286 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inactivation of MntE in S. pneumoniae reduces nasal colonization and bloodstream invasion in mice, despite increased resistance to reactive oxygen species.

    “Inactivation of the manganese efflux protein MntE in S. pneumoniae reduces nasal colonization and bloodstream invasion in mice, despite an increased resistance to reactive oxygen species [142].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [142] Rosch JW, Gao G, Ridout G, Wang YD, Tuomanen EI (2009) Role of the manganese efflux system mntE for signalling and pathogenesis in Streptococcus pneumoniae. Mol Microbiol 72(1):12–25. doi:10.1111/j.1365-2958.2009.06638.x source

      Not checked in the free run.

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

    Premisecitation

    MntH is a critical virulence determinant for Brucella abortus.

    “The Nramp-type manganese transporter MntH is a critical virulence determinant for Brucella abortus [151].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [151] Anderson ES, Paulley JT, Gaines JM, Valderas MW, Martin DW, Menscher E, Brown TD, Burns CS, Roop RM 2nd (2009) The manganese transporter MntH is a critical virulence determinant for Brucella abortus 2308 in experimentally infected mice. Infect Immun 77(8):3466–3474. doi:10.1128/IAI.00444-09 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    S. aureus uses superoxide dismutase-independent mechanisms to detoxify superoxide, which also depend on manganese.

    “Additionally, S. aureus employs superoxide dismutase-independent mechanisms to detoxify superoxide, a process that is also dependent on manganese [144].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [144] Horsburgh MJ, Wharton SJ, Cox AG, Ingham E, Peacock S, Foster SJ (2002) MntR modulates expression of the PerR regulon and superoxide resistance in Staphylococcus aureus through control of manganese uptake. Mol Microbiol 44(5):1269–1286 source

      Not checked in the free run.

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

    Premisecitation

    Manganese acquisition is required for intracellular survival and virulence of Salmonella enterica.

    “Similarly, acquisition of manganese is required for intracellular survival and virulence of Salmonella enterica [152].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Boyer E, Bergevin I, Malo D, Gros P, Cellier MF (2002) Acquisition of Mn(II) in addition to Fe(II) is required for full virulence of Salmonella enterica serovar Typhimurium. Infect Immun 70(11):6032–6042 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Disruption of MntABC in Neisseria gonorrhoeae reduces intracellular survival and biofilm formation.

    “Disruption of MntABC in Neisseria gonorrhoeae reduces intracellular survival and biofilm formation [153].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] Lim KH, Jones CE, vanden Hoven RN, Edwards JL, Falsetta ML, Apicella MA, Jennings MP, McEwan AG (2008) Metal binding specificity of the MntABC permease of Neisseria gonorrhoeae and its influence on bacterial growth and interaction with cervical epithelial cells. Infect Immun 76(8):3569–3576. doi:10.1128/IAI.01725-07 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nramp1 is an integral membrane protein expressed by professional phagocytes.

    “Nramp1 is an integral membrane protein expressed by professional phagocytes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157] Gruenheid S, Pinner E, Desjardins M, Gros P (1997) Natural resistance to infection with intracellular pathogens: the Nramp1 protein is recruited to the membrane of the phagosome. J Exp Med 185(4):717–730 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Upon phagocytosis, Nramp1 is recruited to the phagosome and remains during maturation into phagolysosomes.

    “Upon phagocytosis, Nramp1 is recruited to the phagosome, where it remains during the maturation of phagosomes into phagolysosomes [157].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157] Gruenheid S, Pinner E, Desjardins M, Gros P (1997) Natural resistance to infection with intracellular pathogens: the Nramp1 protein is recruited to the membrane of the phagosome. J Exp Med 185(4):717–730 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nramp1 may also transport other cations such as iron and zinc, and thus may limit multiple metals to intracellular pathogens.

    “Additional studies suggest that Nramp1 may also transport other cations such as iron and zinc [159, 160], and therefore may participate in limitation of multiple metals to intracellular pathogens.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [159] Forbes JR, Gros P (2003) Iron, manganese, and cobalt transport by Nramp1 (Slc11a1) and Nramp2 (Slc11a2) expressed at the plasma membrane. Blood 102(5):1884–1892. doi:10.1182/blood-2003-02-0425 source

      Not checked in the free run.

    • cites [160] Goswami T, Bhattacharjee A, Babal P, Searle S, Moore E, Li M, Blackwell JM (2001) Natural-resistance-associated macrophage protein 1 is an H+/bivalent cation antiporter. Biochem J 354(Pt 3):511–519 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Abscesses in calprotectin-deficient mice contain manganese levels equivalent to surrounding tissue and have significantly increased bacterial burdens compared with wild-type mice.

    “In contrast, abscesses in mice lacking calprotectin contain manganese levels equivalent to those of surrounding tissue, as well as significantly increased bacterial burdens compared with wild-type mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Corbin BD, Seeley EH, Raab A, Feldmann J, Miller MR, Torres VJ, Anderson KL, Dattilo BM, Dunman PM, Gerads R, Caprioli RM, Nacken W, Chazin WJ, Skaar EP (2008) Metal chelation and inhibition of bacterial growth in tissue abscesses. Science 319(5865):962–965. doi:10.1126/science.1152449 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Calprotectin-treated S. aureus is more susceptible to killing by neutrophils, which exert antimicrobial activity partly through reactive oxygen species.

    “This renders calprotectin-treated S. aureus more susceptible to killing by neutrophils, which exert antimicrobial activity partly through the generation of reactive oxygen species (Fig. 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Zinc supplementation in children reduces duration and severity of acute diarrhea and incidence of lower respiratory tract infection.

    “In children, zinc supplementation reduces the duration and severity of acute diarrhea, and reduces the incidence of lower respiratory tract infection [191–193].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [191] Sazawal S, Black RE, Bhan MK, Bhandari N, Sinha A, Jalla S (1995) Zinc supplementation in young children with acute diarrhea in India. N Engl J Med 333(13):839–844. doi:10.1056/NEJM199509283331304 source

      Not checked in the free run.

    • cites [192] Sazawal S, Black RE, Jalla S, Mazumdar S, Sinha A, Bhan MK (1998) Zinc supplementation reduces the incidence of acute lower respiratory infections in infants and preschool children: a double-blind, controlled trial. Pediatrics 102(1 Pt 1):1–5 source

      Not checked in the free run.

    • cites [193] Lassi ZS, Haider BA, Bhutta ZA (2010) Zinc supplementation for the prevention of pneumonia in children aged 2 months to 59 months. Cochrane Database Syst Rev (12):CD005978. doi:10.1002/14651858.CD005978.pub2 source

      Not checked in the free run.

    • Rests on an assumption: Zinc is an essential nutrient for humans.

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

    Premisecitation

    Czc-type exporters have been postulated to mediate zinc efflux in other bacteria, including P. aeruginosa and S. aureus.

    “Czc-type exporters have subsequently been postulated to mediate efflux of zinc in other bacteria, including P. aeruginosa and S. aureus [146, 202].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [146] Kuroda M, Hayashi H, Ohta T (1999) Chromosome-determined zinc-responsible operon czr in Staphylococcus aureus strain 912. Microbiol Immunol 43(2):115–125 source

      Not checked in the free run.

    • cites [202] Hassan MT, van der Lelie D, Springael D, Romling U, Ahmed N, Mergeay M (1999) Identification of a gene cluster, czr, involved in cadmium and zinc resistance in Pseudomonas aeruginosa. Gene 238(2):417–425 source

      Not checked in the free run.

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

    Premisecitation

    A low-affinity zinc transporter, ZupT, was identified in E. coli based on similarity to eukaryotic ZIP family transporters.

    “A low-affinity zinc transporter, ZupT, was identified in E. coli based on similarity to eukaryotic zinc transporters of the ZIP family [199].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [199] Grass G, Wong MD, Rosen BP, Smith RL, Rensing C (2002) ZupT is a Zn(II) uptake system in Escherichia coli. J Bacteriol 184(3):864–866 source

      Not checked in the free run.

    • Rests on an assumption: Zinc is also an essential nutrient for bacterial pathogens.

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

    Premisecitation

    ZnuABC is a high-affinity ABC-type zinc transporter best characterized in E. coli.

    “ZnuABC is a high-affinity ABC-type zinc transporter best characterized in E. coli, consisting of a periplasmic binding protein (ZnuA), membrane permease (ZnuB), and ATPase (ZnuC) [196].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [196] Patzer SI, Hantke K (1998) The ZnuABC high-affinity zinc uptake system and its regulator Zur in Escherichia coli. Mol Microbiol 28(6):1199–1210 source

      Not checked in the free run.

    • Rests on an assumption: Zinc is also an essential nutrient for bacterial pathogens.

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

    Premisecitation

    CzcCBA in Ralstonia metallidurans mediates efflux of cobalt and cadmium.

    “Another zinc exporter (CzcCBA) was identified in Ralstonia metallidurans, and also mediates efflux of cobalt and cadmium [201].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [201] Nies DH, Silver S (1989) Plasmid-determined inducible efflux is responsible for resistance to cadmium, zinc, and cobalt in Alcaligenes eutrophus. J Bacteriol 171(2):896–900 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Zinc export is essential for homeostasis and is achieved primarily through P-type ATPases.

    “Zinc export is essential for maintenance of homeostasis, and is achieved primarily through P-type ATPases which couple ATP hydrolysis to transport of zinc and other metals across the cell membrane.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [200] Rensing C, Mitra B, Rosen BP (1997) The zntA gene of Escherichia coli encodes a Zn(II)-translocating P-type ATPase. Proc Natl Acad Sci U S A 94(26):14326–14331 source

      Not checked in the free run.

    • cites [201] Nies DH, Silver S (1989) Plasmid-determined inducible efflux is responsible for resistance to cadmium, zinc, and cobalt in Alcaligenes eutrophus. J Bacteriol 171(2):896–900 source

      Not checked in the free run.

    • Rests on an assumption: Zinc concentrations must be carefully regulated, as excess zinc can inappropriately bind to thiol groups of bacterial proteins and interfere with their function.
    • Rests on an assumption: In bacteria, zinc homeostasis is achieved through coordinated regulation of import and export.

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

    Premisecitation

    Zinc-binding proteins constitute an average of 5% of bacterial proteomes and participate in regulation of virulence factors, metabolism, and antibiotic inactivation.

    “Zinc-binding proteins, which constitute an average of 5% of bacterial proteomes [195], participate in diverse processes such as regulation of virulence factors, metabolism, and inactivation of antibiotics.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [195] Andreini C, Banci L, Bertini I, Rosato A (2006) Zinc through the three domains of life. J Proteome Res 5(11):3173–3178. doi:10.1021/pr0603699 source

      Not checked in the free run.

    • Rests on an assumption: Zinc is also an essential nutrient for bacterial pathogens.

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

    Premisecitation

    ZntA in E. coli mediates efflux of both zinc and cadmium.

    “ZntA in E. coli mediates efflux of both zinc and cadmium [200].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [200] Rensing C, Mitra B, Rosen BP (1997) The zntA gene of Escherichia coli encodes a Zn(II)-translocating P-type ATPase. Proc Natl Acad Sci U S A 94(26):14326–14331 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-6 administration to mice leads to hypozincemia and increased hepatic zinc concentration through upregulation of Zip14 in hepatocytes.

    “Similarly, IL-6 administration to mice leads to hypozince-mia and increased hepatic zinc concentration through upregulation of the zinc transporter Zip14 in hepatocytes [207, 208].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [207] Gabay C, Kushner I (1999) Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 340(6):448–454. doi:10.1056/NEJM199902113400607 source

      Not checked in the free run.

    • cites [208] Liuzzi JP, Lichten LA, Rivera S, Blanchard RK, Aydemir TB, Knutson MD, Ganz T, Cousins RJ (2005) Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response. Proc Natl Acad Sci U S A 102(19):6843–6848. doi:10.1073/pnas.0502257102 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Zinc levels within staphylococcal abscesses are unaffected by genetic defects in calprotectin production, suggesting additional host factors contribute to zinc limitation.

    “However, zinc levels within the staphylococcal abscess are unaffected by genetic defects in calprotectin production, raising the possibility that additional host factors contribute to zinc limitation in abscesses [34].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Corbin BD, Seeley EH, Raab A, Feldmann J, Miller MR, Torres VJ, Anderson KL, Dattilo BM, Dunman PM, Gerads R, Caprioli RM, Nacken W, Chazin WJ, Skaar EP (2008) Metal chelation and inhibition of bacterial growth in tissue abscesses. Science 319(5865):962–965. doi:10.1126/science.1152449 source

      Not checked in the free run.

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

    Premisecitation

    In B. subtilis and L. monocytogenes, CopZ interacts and exchanges copper with CopA, and is predicted to protect bacteria from inappropriate copper binding to cytoplasmic proteins.

    “In B. subtilis and L. monocytogenes, CopZ interacts and exchanges copper with CopA, and is therefore predicted to protect bacteria from the inappropriate binding of copper to cytoplasmic proteins [214, 215].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [214] Banci L, Bertini I, Ciofi-Baffoni S, Del Conte R, Gonnelli L (2003) Understanding copper trafficking in bacteria: interaction between the copper transport protein CopZ and the N-terminal domain of the copper ATPase CopA from Bacillus subtilis. Biochemistry 42(7):1939–1949. doi:10.1021/bi027096p source

      Not checked in the free run.

    • cites [215] Radford DS, Kihlken MA, Borrelly GP, Harwood CR, Le Brun NE, Cavet JS (2003) CopZ from Bacillus subtilis interacts in vivo with a copper exporting CPx-type ATPase CopA. FEMS Microbiol Lett 220(1):105–112 source

      Not checked in the free run.

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

    Premisecitation

    Copper-containing biocides have shown promise as hand sanitization gels and environmental disinfectants.

    “Copper-containing biocides have shown promise as hand sanitization gels and environmental disinfectants [226, 227].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [226] Hall TJ, Wren MW, Jeanes A, Gant VA (2009) A comparison of the antibacterial efficacy and cytotoxicity to cultured human skin cells of 7 commercial hand rubs and Xgel, a new copper-based biocidal hand rub. Am J Infect Control 37(4):322–326. doi:10.1016/j.ajic.2008.09.011 source

      Not checked in the free run.

    • cites [227] Gant VA, Wren MW, Rollins MS, Jeanes A, Hickok SS, Hall TJ (2007) Three novel highly charged copper-based biocides: safety and efficacy against healthcare-associated organisms. J Antimicrob Chemother 60(2):294–299. doi:10.1093/jac/dkm201 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Copper-deficient mice exhibit impaired humoral immune response and enhanced susceptibility to bacterial pathogens.

    “The importance of copper to the vertebrate immune response is demonstrated by copper-deficient mice, which exhibit an impaired humoral immune response and enhanced susceptibility to a variety of bacterial pathogens [219, 220].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [219] Prohaska JR, Lukasewycz OA (1981) Copper deficiency suppresses the immune response of mice. Science 213(4507):559–561 source

      Not checked in the free run.

    • cites [220] White C, Lee J, Kambe T, Fritsche K, Petris MJ (2009) A role for the ATP7A copper-transporting ATPase in macrophage bactericidal activity. J Biol Chem 284(49):33949–33956. doi:10.1074/jbc.M109.070201 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Vertebrate hosts can increase metal ion concentration in certain environments to kill bacterial pathogens, in addition to nutritional immunity by sequestration.

    “Therefore, in addition to nutritional immunity mediated by metal ion sequestration, vertebrate hosts can increase metal ion concentration in certain environments to kill bacterial pathogens.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    IMS can be used to image single microbial colonies, biofilms, interactions between microbes, and polymicrobial communities.

    “IMS can be used to image single microbial colonies, bacteria growing in biofilms, interactions between two different microbes, and poly-microbial communities [231].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [231] Watrous JD, Dorrestein PC (2011) Imaging mass spectrometry in microbiology. Nat Rev Microbiol 9(9):683–694. doi:10.1038/nrmicro2634 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    LA-ICPMS allows determination of both spatial distribution and absolute concentrations of metal ions in infected tissues.

    “LA-ICPMS therefore allows for determination of both spatial distribution of metal ions as well as their absolute concentrations in a range of infected tissues.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: LA-ICPMS is a highly sensitive form of mass spectroscopy capable of quantifying elemental abundance within two dimensions.

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

    Premisecitation

    IMS has been used to analyze proteins, peptides, lipids, drugs, and metabolites.

    “IMS has been used to analyze proteins, peptides, lipids, drugs, and metabolites [229].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [229] Seeley EH, Caprioli RM (2011) MALDI imaging mass spectrometry of human tissue: method challenges and clinical perspectives. Trends Biotechnol 29(3):136–143. doi:10.1016/j.tibtech.2010.12.002 source

      Not checked in the free run.

    • Rests on an assumption: Whereas sample preparation for conventional proteomic analyses results in disruption of tissue architecture, IMS allows for demonstration of sample distribution in intact tissues.

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

    Premisecitation

    IMS can be combined with MRI to provide three-dimensional co-registration of proteomic data with anatomy.

    “Furthermore, IMS can be combined with additional imaging modalities such as magnetic resonance imaging to provide a three-dimensional co-registration of proteomic data with anatomy [230].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [230] Sinha TK, Khatib-Shahidi S, Yankeelov TE, Mapara K, Ehtesham M, Cornett DS, Dawant BM, Caprioli RM, Gore JC (2008) Integrating spatially resolved three-dimensional MALDI IMS with in vivo magnetic resonance imaging. Nat Methods 5(1):57–59. doi:10.1038/nmeth1147 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    The ability to characterize microbial physiology in vivo and assess host immune responses provides an opportunity for comprehensive study of bacterial infections.

    “The ability to characterize microbial physiology in vivo, together with the capability to assess host immune responses, provides an opportunity for comprehensive study of bacterial infections.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    S. aureus strains inactivated for KatA and AhpC are more sensitive to copper toxicity, supporting oxidative stress as a mechanism for copper-mediated killing.

    “S. aureus strains inactivated for the hydrogen peroxide-reducing enzymes KatA and AhpC are more sensitive to copper toxicity, further supporting oxidative stress as a mechanism for copper-mediated staphylococcal killing.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [228] Baker J, Sitthisak S, Sengupta M, Johnson M, Jayaswal RK, Morrissey JA (2010) Copper stress induces a global stress response in Staphylococcus aureus and represses sae and agr expression and biofilm formation. Appl Environ Microbiol 76(1):150–160. doi:10.1128/AEM.02268-09 source

      Not checked in the free run.

    • Rests on an assumption: Like iron, copper can interact with hydrogen peroxide to generate damaging reactive oxygen species.

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

    Premisecitation

    IMS uses matrix-assisted laser desorption/ionization time of flight to directly analyze molecules in tissue sections.

    “IMS uses matrix-assisted laser desorption/ionization time of flight to directly analyze a variety of molecules in tissue sections.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [229] Seeley EH, Caprioli RM (2011) MALDI imaging mass spectrometry of human tissue: method challenges and clinical perspectives. Trends Biotechnol 29(3):136–143. doi:10.1016/j.tibtech.2010.12.002 source

      Not checked in the free run.

    • Rests on an assumption: Whereas sample preparation for conventional proteomic analyses results in disruption of tissue architecture, IMS allows for demonstration of sample distribution in intact tissues.

  • May combine two claims.

    Premisecitation

    In response to copper exposure, S. aureus induces oxidative stress and misfolded protein responses, suggesting copper toxicity causes oxidative stress and protein damage.

    “In response to copper exposure, S. aureus initiates a transcriptional program characterized by induction of oxidative stress and misfolded protein responses, suggesting that copper toxicity results in increased oxidative stress and protein damage [228].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [228] Baker J, Sitthisak S, Sengupta M, Johnson M, Jayaswal RK, Morrissey JA (2010) Copper stress induces a global stress response in Staphylococcus aureus and represses sae and agr expression and biofilm formation. Appl Environ Microbiol 76(1):150–160. doi:10.1128/AEM.02268-09 source

      Not checked in the free run.

    • Rests on an assumption: Like iron, copper can interact with hydrogen peroxide to generate damaging reactive oxygen species.

  • May combine two claims.

    Interpretationreasoning

    Iron acquisition is critical to S. aureus virulence and is an attractive target for new antimicrobials and vaccines.

    “Iron acquisition is critical to S. aureus virulence, and therefore is an attractive target for the development of new antimicrobials and vaccines.”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    The success of S. aureus as a human pathogen is facilitated by its ability to infect and survive within diverse host tissues.

    “The success of S. aureus as a human pathogen is facilitated by its ability to infect and survive within diverse host tissues.”
    Quote in the paperNot a substantial claim
70 of 70

  • The paper relies on this without support.

    Iron is necessary for bacterial proliferation.

    “Since iron is necessary for bacterial proliferation, S. aureus must circumvent iron sequestration in order to successfully infect host tissues.”

  • The paper relies on this without support.

    Extracellular iron released in vertebrates is tightly bound by transferrin and lactoferrin.

    “Furthermore, any iron released into the extracellular environment is tightly bound to the high-affinity iron-scavenging glycoproteins transferrin and lactoferrin.”

  • The paper relies on this without support.

    S. aureus is predominantly an extracellular pathogen.

    “The majority of vertebrate iron is therefore inaccessible to predominantly extracellular pathogens such as S. aureus.”

  • The paper relies on this without support.

    Manganese is an essential nutrient for both eukaryotic and prokaryotic organisms.

    “Manganese is an essential nutrient for both eukaryotic and prokaryotic organisms.”

  • The paper relies on this without support.

    Zinc is an essential nutrient for humans.

    “Zinc is an essential nutrient for humans.”

  • The paper relies on this without support.

    Zinc is also an essential nutrient for bacterial pathogens.

    “Zinc is also an essential nutrient for bacterial pathogens.”

  • The paper relies on this without support.

    Zinc concentrations must be carefully regulated, as excess zinc can inappropriately bind to thiol groups of bacterial proteins and interfere with their function.

    “Zinc concentrations must be carefully regulated, as excess zinc can inappropriately bind to thiol groups of bacterial proteins and interfere with their function.”

  • The paper relies on this without support.

    In bacteria, zinc homeostasis is achieved through coordinated regulation of import and export.

    “In bacteria, zinc homeostasis is achieved through coordinated regulation of import and export.”

  • The paper relies on this without support.

    Bacteria express both high- and low-affinity zinc importers.

    “Bacteria express both high- and low-affinity zinc importers.”

  • The paper relies on this without support.

    Copper is an important cofactor for a number of bacterial enzymes, but like other transition metals, it is toxic if concentrations are not carefully regulated.

    “Copper is an important cofactor for a number of bacterial enzymes, but like other transition metals, it is toxic if concentrations are not carefully regulated.”

  • The paper relies on this without support.

    Like iron, copper can interact with hydrogen peroxide to generate damaging reactive oxygen species.

    “Like iron, copper can interact with hydrogen peroxide to generate damaging reactive oxygen species.”

  • The paper relies on this without support.

    Whereas sample preparation for conventional proteomic analyses results in disruption of tissue architecture, IMS allows for demonstration of sample distribution in intact tissues.

    “Whereas sample preparation for conventional proteomic analyses results in disruption of tissue architecture, IMS allows for demonstration of sample distribution in intact tissues.”

  • The paper relies on this without support.

    LA-ICPMS is a highly sensitive form of mass spectroscopy capable of quantifying elemental abundance within two dimensions.

    “LA-ICPMS is a highly sensitive form of mass spectroscopy capable of quantifying elemental abundance within two dimensions.”

  • The paper relies on this without support.

    Infection of tissues such as bone, lung, or heart may not involve defined abscesses.

    “infection of other tissues such as bone, lung, or heart may not be accompanied by formation of defined abscesses”

  • The paper relies on this without support.

    Essential metal nutrient availability may differ among host tissues.

    “the availability of essential metal nutrients may differ among host tissues”
15 of 15

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?

  • Acquisition of heme by the Isd system is critical for Staphylococcus aureus pathogenesis.

    “Acquisition of heme by the Isd system is critical for S. aureus pathogenesis (Cassat and Skaar, 2012).”

    From Iron in infection and immunity (2013) · cites this paper as Cassat and Skaar, 2012

  • Siderophore production contributes to the virulence of Staphylococcus aureus, Escherichia coli, Legionella pneumophila, and Bacillus anthracis.

    “The production of siderophores contributes to the virulence of a variety of pathogens, including S. aureus, Escherichia coli, Legionella pneumophila, and Bacillus anthracis, among others (Cassat and Skaar, 2012).”

    From Iron in infection and immunity (2013) · cites this paper as Cassat and Skaar, 2012

Cites

1 retracted

Flagged first, then by citations

Research works printed but not linked: 1

  1. Young NS, Gerson SL, High KA (2006) Clinical hematology, vol 1. Mosby Elsevier, Philadelphia

Cited by

Sorted by citations

Related

Authors
Cassat, J. E., & Skaar, E. P.
Affiliations
Vanderbilt University Medical Center (US)
Corresponding author
Skaar, Eric P.
ORCID
Venue
Seminars in Immunopathology
Publisher
Springer Science and Business Media LLC
Published
2011-11-03
Volume
34
Issue
2
Pages
215-235
ISSN
  • 1863-2297 (ISSN-L)
  • 1863-2300
DOI
10.1007/s00281-011-0294-4
PMC
PMC3796439
OpenAlex
W1976196422
Cited by
155
References
232
Citations by year
2026: 16 · 2025: 8 · 2024: 18 · 2023: 7 · 2022: 6 · 2021: 12 · 2020: 18 · 2019: 9 · 2018: 12 · 2017: 8 · 2016: 7 · 2015: 8 · 2014: 8 · 2013: 11 · 2012: 7
FWCI
1.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Seminars in Immunopathology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Burroughs Wellcome Fund
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (AI073843, AI091771, L40 AI096516, AI0169233, R01AI069233, R56AI091771, U54AI057157, R01AI073843, R01AI101171, R21AI107233)
  • National Center for Research Resources (S10RR026742)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD060554)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antimicrobial Resistance in Staphylococcus
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bacterial biofilms and quorum sensing
Keywords
Staphylococcus aureus, nutritional immunity, transition metals, bacterial virulence, antioxidant defense, host-pathogen interaction
MeSH terms
Animals, Copper, Humans, Ions, Manganese, Metals, Mass Spectrometry, Staphylococcal Infections, Staphylococcus aureus, Zinc, Host-Pathogen Interactions

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 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

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