Metal ion acquisition in Staphylococcus aureus: overcoming nutritional immunity

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [32] Weinberg ED (2009) Iron availability and infection. Biochim Biophys Acta 1790(7):600–605. doi:10.1016/j.bbagen.2008.07.002 source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“Fur is an iron-dependent transcriptional regulator that is conserved among Gram-positive and Gram-negative bacteria [50].”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“For example, patients with hemochromatosis are more susceptible to infection by Yersinia enterocolitica, Vibrio vulnificans, and Listeria monocytogenes [39–42].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [41] Weinberg ED (2000) Microbial pathogens with impaired ability to acquire host iron. Biometals 13(1):85–89 source
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [38] Crichton R (2001) Inorganic biochemistry of iron metabolism: from molecular mechanisms to clinical consequences, vol 2. Wiley, West Sussex source

In the paper

“Stealth side-rophores have not been described in S. aureus.”

In the paper

“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].”

What the sources say

• Not checked yetcites [86] Young NS, Gerson SL, High KA (2006) Clinical hematology, vol 1. Mosby Elsevier, Philadelphia
• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“Deletion of either isdG or isdI results in a decreased ability to utilize heme, indicating that these enzymes are not functionally redundant [105].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“Moreover, passive immunization with anti-Hla antibodies or active immunization with nontoxigenic Hla is protective in animal models of staphylococcal infection [108, 115].”

What the sources say

• Not checked yetcites [108] Kennedy AD, Bubeck Wardenburg J, Gardner DJ, Long D, Whitney AR, Braughton KR, Schneewind O, DeLeo FR (2010) Targeting of alpha-hemolysin by active or passive immunization decreases severity of USA300 skin infection in a mouse model. J Infect Dis 202(7):1050–1058. doi:10.1086/656043 source
• Not checked yetcites [115] Ragle BE, Bubeck Wardenburg J (2009) Anti-alpha-hemolysin monoclonal antibodies mediate protection against Staphylococcus aureus pneumonia. Infect Immun 77(7):2712–2718. doi:10.1128/IAI.00115-09 source

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [121] Kuklin NA, Clark DJ, Secore S, Cook J, Cope LD, McNeely T, Noble L, Brown MJ, Zorman JK, Wang XM, Pancari G, Fan H, Isett K, Burgess B, Bryan J, Brownlow M, George H, Meinz M, Liddell ME, Kelly R, Schultz L, Montgomery D, Onishi J, Losada M, Martin M, Ebert T, Tan CY, Schofield TL, Nagy E, Meineke A, Joyce JG, Kurtz MB, Caulfield MJ, Jansen KU, McClements W, Anderson AS (2006) A novel Staphylococcus aureus vaccine: iron surface determinant B induces rapid antibody responses in rhesus macaques and specific increased survival in a murine S. aureus sepsis model. Infect Immun 74(4):2215–2223. doi: source
• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“IsdA binds both fibrinogen and fibronectin in vitro, indicating a potential role as an iron-regulated adhesin [125].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“Consistent with this hypothesis, IsdA facilitates binding to human desquamated epithelial cells, and promotes nasal colonization in rats [122, 126, 127].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“Mutation of isdA also leads to increased susceptibility to hydrogen peroxide and to killing by human neutrophils [129].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“Bacteria, like humans, must acquire manganese and regulate its intracellular concentration.”

What the sources say

• Not checked yetcites [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

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“The S. aureus genome encodes MntABC-type (mntABC) and Nramp-type (mntH) manganese transporters, both of which have been functionally characterized.”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“The Nramp-type manganese transporter MntH is a critical virulence determinant for Brucella abortus [151].”

What the sources say

• Not checked yetcites [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

In the paper

“Additionally, S. aureus employs superoxide dismutase-independent mechanisms to detoxify superoxide, a process that is also dependent on manganese [144].”

What the sources say

• Not checked yetcites [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

In the paper

“Similarly, acquisition of manganese is required for intracellular survival and virulence of Salmonella enterica [152].”

What the sources say

• Not checked yetcites [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

In the paper

“Disruption of MntABC in Neisseria gonorrhoeae reduces intracellular survival and biofilm formation [153].”

What the sources say

• Not checked yetcites [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

In the paper

“Nramp1 is an integral membrane protein expressed by professional phagocytes.”

What the sources say

• Not checked yetcites [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

In the paper

“Upon phagocytosis, Nramp1 is recruited to the phagosome, where it remains during the maturation of phagosomes into phagolysosomes [157].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

In the paper

“In children, zinc supplementation reduces the duration and severity of acute diarrhea, and reduces the incidence of lower respiratory tract infection [191–193].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“Czc-type exporters have subsequently been postulated to mediate efflux of zinc in other bacteria, including P. aeruginosa and S. aureus [146, 202].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“A low-affinity zinc transporter, ZupT, was identified in E. coli based on similarity to eukaryotic zinc transporters of the ZIP family [199].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“Another zinc exporter (CzcCBA) was identified in Ralstonia metallidurans, and also mediates efflux of cobalt and cadmium [201].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“ZntA in E. coli mediates efflux of both zinc and cadmium [200].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“Copper-containing biocides have shown promise as hand sanitization gels and environmental disinfectants [226, 227].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [219] Prohaska JR, Lukasewycz OA (1981) Copper deficiency suppresses the immune response of mice. Science 213(4507):559–561 source
• Not checked yetcites [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

In the paper

“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.”

In the paper

“IMS can be used to image single microbial colonies, bacteria growing in biofilms, interactions between two different microbes, and poly-microbial communities [231].”

What the sources say

• Not checked yetcites [231] Watrous JD, Dorrestein PC (2011) Imaging mass spectrometry in microbiology. Nat Rev Microbiol 9(9):683–694. doi:10.1038/nrmicro2634 source

In the paper

“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.”

In the paper

“IMS has been used to analyze proteins, peptides, lipids, drugs, and metabolites [229].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

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