The lipoprotein components of the Isd and Hts transport systems are dispensable for acquisition of heme by Staphylococcus aureus
Abstract
Heme is a key molecule for Staphylococcus aureus and is involved in many aspects of oxidative metabolism. Crucially, heme is required for the activity of cytochromes of the electron transport chain. Staphylococcus aureus is able to obtain heme either through biosynthesis or through acquisition from the host. Clinically persistent 'small colony variant' (SCV) forms of S. aureus are frequently deficient for heme biosynthesis, and disruption of the hemB gene produces stable heme-auxotrophic strains that reproduce many SCV phenotypes. We sought to address the role of heme transport in SCVs by deleting components of the two described heme import systems, the iron-regulated surface determinant (Isd) and heme transport system (Hts) in wild-type S. aureus and hemB mutant backgrounds. Analysis of the growth of S. aureus hemB strains either singly or doubly deficient in isdE and htsA in the presence and absence of heme or hemoglobin revealed that S. aureus is able to obtain exogenous heme in the absence of these transporter components. These data suggest the presence of additional, as yet unidentified transporter components that enable S. aureus to internalize exogenous heme and contradict the proposed model that IsdE can transfer heme to the HtsBC permease.
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Two recent reports challenged the large literature on the Isd system's role in hemoglobin/heme-derived iron acquisition.
“However, the wealth of literature on the contribution of the Isd system to hemoglobin/heme-derived iron acquisition was challenged by 2 recent reports [36, 37].”
From IsdB-dependent hemoglobin binding is required for acquisition of heme by Staphylococcus aureus (2014) · cites this paper as [37]
Cites
Exotoxins of Staphylococcus aureus
Dinges, M. M., Orwin, P. M., & Schlievert, P. M. (2000) · Clinical Microbiology Reviews · doi:10.1128/cmr.13.1.16-34.2000 · Cited by 1,571 · see citing works
The toxic shock syndrome exotoxin structural gene is not detectably transmitted by a prophage
Kreiswirth, B. N., Löfdahl, S., Betley, M. J., O’Reilly, M., Schlievert, P. M., Bergdoll, M. S., & Novick, R. P. (1983) · Nature · doi:10.1038/305709a0 · Cited by 1,327 · see citing works
Proctor, R. A., von Eiff, C., Kahl, B. C., Becker, K., McNamara, P., Herrmann, M., & Peters, G. (2006) · Nature Reviews Microbiology · doi:10.1038/nrmicro1384 · Cited by 1,175 · see citing works
DNA Cloning Using In Vitro Site-Specific RecombinationPreprint
Hartley, J. L. (2000) · Genome Research · doi:10.1101/gr.143000 · Cited by 1,134 · see citing works
The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration?
Beutler, E., & Waalen, J. (2005) · Blood · doi:10.1182/blood-2005-07-3046 · Cited by 971 · see citing works
Allelic replacement in Staphylococcus aureus with inducible counter-selection
Bae, T., & Schneewind, O. (2005) · Plasmid · doi:10.1016/j.plasmid.2005.05.005 · Cited by 624 · see citing works
Passage of Heme-Iron Across the Envelope of <i>Staphylococcus aureus</i>
Mazmanian, S. K., Skaar, E. P., Gaspar, A. H., Humayun, M., Gornicki, P., Jelenska, J., Joachmiak, A., Missiakas, D. M., & Schneewind, O. (2003) · Science · doi:10.1126/science.1081147 · Cited by 593 · see citing works
Iron-Source Preference of <i>Staphylococcus aureus</i> Infections
Skaar, E. P., Humayun, M., Bae, T., DeBord, K. L., & Schneewind, O. (2004) · Science · doi:10.1126/science.1099930 · Cited by 440 · see citing works
Persistent and Relapsing Infections Associated with Small-Colony Variants of Staphylococcus aureus
Proctor, R. A., van Langevelde, P., Kristjansson, M., Maslow, J. N., & Arbeit, R. D. (1995) · Clinical Infectious Diseases · doi:10.1093/clinids/20.1.95 · Cited by 437 · see citing works
Molecular Mechanisms of <i>Staphylococcus aureus</i> Iron Acquisition
Hammer, N. D., & Skaar, E. P. (2011) · Annual Review of Microbiology · doi:10.1146/annurev-micro-090110-102851 · Cited by 379 · see citing works
McrA and McrB restriction phenotypes of someE.colistrains and implications for gene cloning
Raleigh, E. A., Murray, N. E., Revel, H. R. B., Blumenthal, R., Westaway, D. A., Reith, A. D., Rigby, P. W. J., Elhai, J., & Hanahan, D. (1988) · Nucleic Acids Research · doi:10.1093/nar/16.4.1563 · Cited by 342 · see citing works
von Eiff, C., Heilmann, C., Proctor, R. A., Woltz, C., Peters, G., & Götz, F. (1997) · Journal of Bacteriology · doi:10.1128/jb.179.15.4706-4712.1997 · Cited by 310 · see citing works
<i>Staphylococcus aureus</i> IsdB Is a Hemoglobin Receptor Required for Heme Iron Utilization
Torres, V. J., Pishchany, G., Humayun, M., Schneewind, O., & Skaar, E. P. (2006) · Journal of Bacteriology · doi:10.1128/jb.01335-06 · Cited by 302 · see citing works
Waldron, D. E., & Lindsay, J. A. (2006) · Journal of Bacteriology · doi:10.1128/jb.00418-06 · Cited by 298 · see citing works
Staphylococcus aureus as an intracellular pathogen: the role of small colony variants
Sendi, P., & Proctor, R. A. (2009) · Trends in Microbiology · doi:10.1016/j.tim.2008.11.004 · Cited by 281 · see citing works
von Eiff, C., Bettin, D., Proctor, R. A., Rolauffs, B., Lindner, N. J., Winkelmann, W., & Peters, G. (1997) · Clinical Infectious Diseases · doi:10.1086/516962 · Cited by 249 · see citing works
The Staphylococcus aureus surface protein IsdA mediates resistance to innate defenses of human skin
Clarke, S. R., Mohamed, R., Bian, L., Routh, A. F., Kokai-Kun, J. F., Mond, J. J., Tarkowski, A., & Foster, S. J. (2007) · Cell Host & Microbe · doi:10.1016/j.chom.2007.04.005 · Cited by 225 · see citing works
Gao, W., Chua, K., Davies, J. K., Newton, H. J., Seemann, T., Harrison, P. F., Holmes, N. E., Rhee, H., Hong, J., Hartland, E. L., et al. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1000944 · Cited by 218 · see citing works
Vaudaux, P. E., François, P., Bisognano, C., Kelley, W. L., Lew, D. P., Schrenzel, J., Proctor, R. A., McNamara, P. J., Peters, G., & von Eiff, C. (2002) · Infection and Immunity · doi:10.1128/iai.70.10.5428-5437.2002 · Cited by 185 · see citing works
The small colony variant (SCV) concept—the role of staphylococcal SCVs in persistent infections
von Eiff, C., Peters, G., & Becker, K. (2006) · Injury · doi:10.1016/j.injury.2006.04.006 · Cited by 181 · see citing works
Kahl, B. C., Dübbers, A., Lubritz, G., Haeberle, J., Koch, H. G., Ritzerfeld, B., Reilly, M., Harms, E., Proctor, R. A., Herrmann, M., et al. (2003) · Journal of Clinical Microbiology · doi:10.1128/jcm.41.9.4424-4427.2003 · Cited by 175 · see citing works
Beasley, F. C., Vinés, E. D., Grigg, J. C., Zheng, Q., Liu, S., Lajoie, G. A., Murphy, M. E. P., & Heinrichs, D. E. (2009) · Molecular Microbiology · doi:10.1111/j.1365-2958.2009.06698.x · Cited by 163 · see citing works
Dryla, A., Gelbmann, D., Von Gabain, A., & Nagy, E. (2003) · Molecular Microbiology · doi:10.1046/j.1365-2958.2003.03542.x · Cited by 153 · see citing works
IsdA of <i>Staphylococcus aureus</i> is a broad spectrum, iron‐regulated adhesin
Clarke, S. R., Wiltshire, M. D., & Foster, S. J. (2004) · Molecular Microbiology · doi:10.1111/j.1365-2958.2003.03938.x · Cited by 150 · see citing works
Nguyen, H. D., Nguyễn, Q. A., Ferreira, R. D. C. C., et al. (2005) · Plasmid · doi:10.1016/j.plasmid.2005.05.001 · Cited by 149 · see citing works
Why Heme Needs to Be Degraded to Iron, Biliverdin IXα, and Carbon Monoxide?
Sassa, S. (2004) · Antioxidants and Redox Signaling · doi:10.1089/ars.2004.6.819 · Cited by 145 · see citing works
Muryoi, N., Tiedemann, M. T., Pluym, M., Cheung, J., Heinrichs, D. E., & Stillman, M. J. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m802171200 · Cited by 144 · see citing works
Köhler, C., von Eiff, C., Peters, G., Proctor, R. A., Hecker, M., & Engelmann, S. (2003) · Journal of Bacteriology · doi:10.1128/jb.185.23.6928-6937.2003 · Cited by 133 · see citing works
Physiology and Antibiotic Susceptibility of <i>Staphylococcus aureus</i> Small Colony Variants
Baumert, N., von Eiff, C., Schaaff, F., Peters, G., Proctor, R. A., & Sahl, H.-G. (2002) · Microbial Drug Resistance · doi:10.1089/10766290260469507 · Cited by 130 · see citing works
von Eiff, C., McNamara, P. J., Becker, K., Bates, D. M., Lei, X.-H., Ziman, M., Bochner, B. R., Peters, G., & Proctor, R. A. (2005) · Journal of Bacteriology · doi:10.1128/jb.188.2.687-693.2006 · Cited by 129 · see citing works
Zhu, H., Xie, G., Liu, M., Olson, J. S., Fabian, M., Dooley, D. M., & Lei, B. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m801466200 · Cited by 127 · see citing works
Bates, D. M., Eiff, C. V., McNamara, P. J., Peters, G., Yeaman, M. R., Bayer, A. S., & Proctor, R. A. (2003) · The Journal of Infectious Diseases · doi:10.1086/374642 · Cited by 106 · see citing works
Clarke, S. R., Andre, G., Walsh, E. J., Dufrêne, Y. F., Foster, T. J., & Foster, S. J. (2009) · Infection and Immunity · doi:10.1128/iai.01304-08 · Cited by 105 · see citing works
Miajlović, H., Zapotoczna, M., Geoghegan, J. A., Kerrigan, S. W., Speziale, P., & Foster, T. J. (2009) · Microbiology · doi:10.1099/mic.0.036673-0 · Cited by 104 · see citing works
Heme Coordination by Staphylococcus aureus IsdE
Grigg, J. C., Vermeiren, C. L., Heinrichs, D. E., & Murphy, M. E. P. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704602200 · Cited by 96 · see citing works
Repression and catabolite repression of the lactose operon of Staphylococcus aureus
Oskouian, B., & Stewart, G. C. (1990) · Journal of Bacteriology · doi:10.1128/jb.172.7.3804-3812.1990 · Cited by 88 · see citing works
Regulation of the enterotoxin B gene in Staphylococcus aureus.
Gaskill, M. E., & Khan, S. A. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)68782-4 · Cited by 86 · see citing works
Small Colony Variants of Staphylococcus aureus and Pacemaker-related Infection
Seifert, H., Wisplinghoff, H., Schnabel, P., & von Eiff, C. (2003) · Emerging infectious diseases · doi:10.3201/eid0910.0302000 · Cited by 84 · see citing works
Seggewiß, J., Becker, K., Kotte, O., Eisenacher, M., Yazdi, M. R. K., Fischer, A., McNamara, P. J., Laham, N. A., Proctor, R. A., Peters, G., et al. (2006) · Journal of Bacteriology · doi:10.1128/jb.00774-06 · Cited by 83 · see citing works
Pathogenic bacteria prefer heme.
Rouault, T. A. (2004) · Science · doi:10.1126/science.1102975 · Cited by 76 · see citing works
Grigg, J. C., Cooper, J. D., Cheung, J., Heinrichs, D. E., & Murphy, M. E. P. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.097865 · Cited by 75 · see citing works
Clarke, S. R., & Foster, S. J. (2008) · Infection and Immunity · doi:10.1128/iai.01530-07 · Cited by 75 · see citing works
Jonsson, I., von Eiff, C., Proctor, R. A., Peters, G., Rydèn, C., & Tarkowski, A. (2003) · Microbial Pathogenesis · doi:10.1016/s0882-4010(02)00208-5 · Cited by 66 · see citing works
Structural Basis for Hemoglobin Capture by Staphylococcus aureus Cell-surface Protein, IsdH
Kumar, K. K., Jacques, D. A., Pishchany, G., Caradoc-Davies, T. T., Spirig, T., Malmirchegini, G. R., Langley, D. B., Dickson, C. F., Mackay, J. P., Clubb, R., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.287300 · Cited by 58 · see citing works
Spanu, T., Romano, L., D’Inzeo, T., Masucci, L., Albanese, A., Papacci, F., Marchese, E., Sanguinetti, M., & Fadda, G. (2005) · Clinical Infectious Diseases · doi:10.1086/432577 · Cited by 54 · see citing works
Tsuji, B. T., von Eiff, C., Kelchlin, P. A., Forrest, A., & Smith, P. F. (2008) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01254-07 · Cited by 51 · see citing works
Gómez-González, C., Acosta, J., Villa, J., Barrado, L., Sanz, F., Orellana, M. Á., Otero, J. R., & Cháves, F. (2010) · Journal of Clinical Microbiology · doi:10.1128/jcm.00520-10 · Cited by 49 · see citing works
Mason, W. J., & Skaar, E. P. (2009) · PLoS ONE · doi:10.1371/journal.pone.0006668 · Cited by 28 · see citing works
Cloning and sequence analysis of the hemB gene of Staphylococcus aureus
Kafala, B., & Sasarman, A. (1994) · Canadian Journal of Microbiology · doi:10.1139/m94-103 · Cited by 16 · see citing works
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IsdB-dependent hemoglobin binding is required for acquisition of heme by Staphylococcus aureus
Pishchany, G., Sheldon, J. R., Dickson, C. F., Alam, M. T., Read, T. D., Gell, D. A., Heinrichs, D. E., & Skaar, E. P. (2014) · The Journal of Infectious Diseases · doi:10.1093/infdis/jit817 · Cited by 88 · see citing works
- Authors
- Wright, J. A., & Nair, S. P.
- Affiliations
- University College London (GB)
- Corresponding author
- Nair, Sean P.
- Venue
- FEMS Microbiology Letters
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-02-23
- Volume
- 329
- Issue
- 2
- Pages
- 177-185
- ISSN
- 0378-1097 (ISSN-L)
- OpenAlex
- W2018849855
- Cited by
- 17
- References
- 49
- Citations by year
- 2025: 2 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 2 · 2017: 2 · 2016: 1 · 2015: 1 · 2014: 2 · 2013: 2 · 2012: 1
- FWCI
- 1.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- FEMS Microbiology Letters (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Versus Arthritis (18294)
- 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 › Cell Biology › Hemoglobin structure and function
- Keywords
- Staphylococcus aureus, heme acquisition, small colony variants, hemoglobin, bacterial transporters
- MeSH terms
- Porphobilinogen Synthase, Bacterial Proteins, Biological Transport, Active, Carrier Proteins, Culture Media, Escherichia coli, Heme, Humans, Lipoproteins, Mutation, Phenotype, Staphylococcus aureus, Gene Deletion
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