Role of Copper Efflux in Pneumococcal Pathogenesis and Resistance to Macrophage-Mediated Immune Clearance
Open accessAbstract
In bacteria, the intracellular levels of metals are mediated by tightly controlled acquisition and efflux systems. This is particularly true of copper, a trace element that is universally toxic in excess. During infection, the toxic properties of copper are exploited by the mammalian host to facilitate bacterial clearance. To better understand the role of copper during infection, we characterized the contribution of the cop operon to copper homeostasis and virulence in Streptococcus pneumoniae. Deletion of either the exporter, encoded by copA, or the chaperone, encoded by cupA, led to hypersensitivity to copper stress. We further demonstrated that loss of the copper exporter encoded by copA led to decreased virulence in pulmonary, intraperitoneal, and intravenous models of infection. Deletion of copA resulted in enhanced macrophage-mediated bacterial clearance in vitro. The attenuation phenotype of the copA mutant in the lung was found to be dependent on pulmonary macrophages, underscoring the importance of copper efflux in evading immune defenses. Overall, these data provide insight into the role of the cop operon in pneumococcal pathogenesis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In animal models, copper deficiency reduces macrophage-mediated killing of S. pneumoniae, M. tuberculosis, P. haemolytica, and S. Typhimurium.
“In animal models copper deficiency limits macrophage-mediated bactericidal killing against S. pneumoniae, M. tuberculosis, P. haemolytica, and S. Typhimurium (Johnson et al., 2015; Jones and Suttle, 1983; Newberne et al., 1968; Wolschendorf et al., 2011).”
From The Impact of Dietary Transition Metals on Host-Bacterial Interactions (2018) · cites this paper as Johnson et al., 2015
Bacteria have developed ways to counter host copper stress, including copper exporters.
“In response, bacteria have evolved mechanisms to relieve host-mediated copper stress including copper exporters (Johnson et al., 2015).”
From The Impact of Dietary Transition Metals on Host-Bacterial Interactions (2018) · cites this paper as Johnson et al., 2015
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Siderophores: Structure and Function of Microbial Iron Transport Compounds
Neilands, J. B. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.45.26723 · Cited by 1,652 · see citing works
Gene Splicing by Overlap Extension: Tailor-Made Genes Using the Polymerase Chain Reaction
Horton, R. M., Cai, Z., Ho, S. N., & Pease, L. R. (2013) · BioTechniques · doi:10.2144/000114017 · Cited by 1,292 · see citing works
Iron in infection and immunity
Cassat, J. E., & Skaar, E. P. (2013) · Cell Host & Microbe · doi:10.1016/j.chom.2013.04.010 · Cited by 1,214 · see citing works
The iron-sulfur clusters of dehydratases are primary intracellular targets of copper toxicity
Macomber, L., & Imlay, J. A. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0812808106 · Cited by 1,117 · see citing works
Molecular Basis of Metal-Ion Selectivity and Zeptomolar Sensitivity by CueR
Changela, A., Chen, K., Xue, Y., Holschen, J., Outten, C. E., O’Halloran, T. V., & Mondragón, A. (2003) · Science · doi:10.1126/science.1085950 · Cited by 658 · see citing works
Nutritional immunity beyond iron: a role for manganese and zinc
Kehl-Fie, T. E., & Skaar, E. P. (2010) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2009.11.008 · Cited by 634 · see citing works
Self-citationLarge-scale identification of serotype 4 Streptococcus pneumoniae virulence factors
Hava, D. L., & Camilli, A. (2002) · Molecular Microbiology · doi:10.1046/j.1365-2958.2002.t01-1-03106.x · Cited by 605 · see citing works
A Role for the ATP7A Copper-transporting ATPase in Macrophage Bactericidal Activity
White, C., Lee, J., Kambe, T., Fritsche, K., & Petris, M. J. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.070201 · Cited by 524 · see citing works
CopA: An Escherichia coli Cu(I)-translocating P-type ATPase
Rensing, C., Fan, B., Sharma, R., Mitra, B., & Rosen, B. P. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.2.652 · Cited by 517 · see citing works
A pneumococcal pilus influences virulence and host inflammatory responses
Barocchi, M. A., Ries, J., Zogaj, X., Hemsley, C. J., Albiger, B., Kanth, A., Dahlberg, S., Fernebro, J., Moschioni, M., Masignani, V., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0511017103 · Cited by 474 · see citing works
Liposomes for Specific Depletion of Macrophages from Organs and Tissues
van Rooijen, N., & van Kesteren-Hendrikx, E. M. L. (2009) · Methods in molecular biology · doi:10.1007/978-1-60327-360-2_13 · Cited by 381 · see citing works
Percival, S. (1998) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/67.5.1064s · Cited by 370 · see citing works
Tissue‐Specific Contributions of Pneumococcal Virulence Factors to Pathogenesis
Orihuela, C. J., Gao, G., Francis, K. P., Yu, J., & TUOMANEN, E. I. (2004) · The Journal of Infectious Diseases · doi:10.1086/424596 · Cited by 327 · see citing works
Bacterial zinc uptake and regulators
Hantke, K. (2005) · Current Opinion in Microbiology · doi:10.1016/j.mib.2005.02.001 · Cited by 319 · see citing works
Copper Homeostasis at the Host-Pathogen Interface
Hodgkinson, V., & Petris, M. J. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.r111.316406 · Cited by 316 · see citing works
The immune system as a physiological indicator of marginal copper status?
Bonham, M. P., O’Connor, J. M., HANNIGAN, B. M., & Strain, J. J. (2002) · British Journal Of Nutrition · doi:10.1079/bjn2002558 · Cited by 290 · see citing works
Brown, J. S., Gilliland, S. M., & Holden, D. W. (2001) · Molecular Microbiology · doi:10.1046/j.1365-2958.2001.02414.x · Cited by 288 · see citing works
Pericone, C. D., Park, S., Imlay, J. A., & Weiser, J. N. (2003) · Journal of Bacteriology · doi:10.1128/jb.185.23.6815-6825.2003 · Cited by 270 · see citing works
Pyruvate oxidase, as a determinant of virulence in Streptococcus pneumoniae
Spellerberg, B., Cundell, D. R., Sandros, J., Pearce, B. J., Idänpään‐Heikkilä, I., Rosenow, C., & Masure, H. R. (1996) · Molecular Microbiology · doi:10.1046/j.1365-2958.1996.425954.x · Cited by 264 · see citing works
Metal Binding Affinity and Selectivity in Metalloproteins: Insights from Computational Studies
Dudev, T., & Lim, C. (2008) · Annual Review of Biophysics · doi:10.1146/annurev.biophys.37.032807.125811 · Cited by 232 · see citing works
A fine scale phenotype–genotype virulence map of a bacterial pathogenPreprint
van Opijnen, T., & Camilli, A. (2012) · Genome Research · doi:10.1101/gr.137430.112 · Cited by 220 · see citing works
CtpV: a putative copper exporter required for full virulence of Mycobacterium tuberculosis
Ward, S. K., Abomoelak, B., Hoye, E. A., Steinberg, H. N., & Talaat, A. M. (2010) · Molecular Microbiology · doi:10.1111/j.1365-2958.2010.07273.x · Cited by 198 · see citing works
Cryptococcus neoformans copper detoxification machinery is critical for fungal virulence
Ding, C., Festa, R. A., Chen, Y.-L., Espart, A., Palacios, Ò., Espín, J., Capdevila, M., Atrian, S., Heitman, J., & Thiele, D. J. (2013) · Cell Host & Microbe · doi:10.1016/j.chom.2013.02.002 · Cited by 179 · see citing works
Xin, Z., Waterman, D. F., Hemken, R. W., & Harmon, R. J. (1991) · Journal of Dairy Science · doi:10.3168/jds.s0022-0302(91)78493-2 · Cited by 169 · see citing works
Copper redistribution in murine macrophages in response to Salmonella infection
Achard, M. E. S., Stafford, S. L., Bokil, N. J., Chartres, J. D., Bernhardt, P. V., Schembri, M. A., Sweet, M. J., & McEwan, A. G. (2012) · Biochemical Journal · doi:10.1042/bj20112180 · Cited by 160 · see citing works
Shafeeq, S., Yesilkaya, H., Kloosterman, T. G., Narayanan, G., Wandel, M., Andrew, P. W., Kuipers, O. P., & Morrissey, J. A. (2011) · Molecular Microbiology · doi:10.1111/j.1365-2958.2011.07758.x · Cited by 157 · see citing works
Copper Transport and Trafficking at the Host–Bacterial Pathogen Interface
Fu, Y., Chang, F.-M. J., & Giedroc, D. P. (2014) · Accounts of Chemical Research · doi:10.1021/ar500300n · Cited by 146 · see citing works
Biochemical Characterization of CopA, the Escherichia coli Cu(I)-translocating P-type ATPase
Fan, B., & Rosen, B. P. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208490200 · Cited by 141 · see citing works
Molecular analysis of the psa permease complex of Streptococcus pneumoniae
McAllister, L. J., Tseng, H., Ogunniyi, A. D., Jennings, M. P., McEwan, A. G., & Paton, J. C. (2004) · Molecular Microbiology · doi:10.1111/j.1365-2958.2004.04164.x · Cited by 138 · see citing works
Bayle, L., Chimalapati, S., Schoehn, G., Brown, J., Vernet, T., & Durmort, C. (2011) · Molecular Microbiology · doi:10.1111/j.1365-2958.2011.07862.x · Cited by 137 · see citing works
Distinct functional roles of homologous Cu+ efflux ATPases in Pseudomonas aeruginosa
González‐Guerrero, M., Raimunda, D., Cheng, X., & ARGÜELLO, J. M. (2010) · Molecular Microbiology · doi:10.1111/j.1365-2958.2010.07402.x · Cited by 136 · see citing works
Rosch, J. W., Gao, G., Ridout, G., Wang, Y., & Tuomanen, E. I. (2009) · Molecular Microbiology · doi:10.1111/j.1365-2958.2009.06638.x · Cited by 134 · see citing works
Self-citationResistance mechanisms of Mycobacterium tuberculosis against phagosomal copper overload
Rowland, J. L., & Niederweis, M. (2012) · Tuberculosis · doi:10.1016/j.tube.2011.12.006 · Cited by 131 · see citing works
Kloosterman, T. G., van der Kooi‐Pol, M. M., Bijlsma, J. J. E., & Kuipers, O. P. (2007) · Molecular Microbiology · doi:10.1111/j.1365-2958.2007.05849.x · Cited by 128 · see citing works
Recent developments in copper and zinc homeostasis in bacterial pathogens
Braymer, J. J., & Giedroc, D. P. (2014) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2013.12.021 · Cited by 126 · see citing works
Raimunda, D., González‐Guerrero, M., Leeber, B. W., & ARGÜELLO, J. M. (2011) · BioMetals · doi:10.1007/s10534-010-9404-3 · Cited by 118 · see citing works
Large‐scale identification of serotype 4 Streptococcus pneumoniae virulence factors
Hava, D. L., & Camilli, A. (2002) · Molecular Microbiology · doi:10.1046/j.1365-2958.2002.03106.x · Cited by 118 · see citing works
Interplay between manganese and zinc homeostasis in the human pathogen Streptococcus pneumoniae
Jacobsen, F. E., Kazmierczak, K. M., Lisher, J. P., Winkler, M. E., & Giedroc, D. P. (2010) · Metallomics · doi:10.1039/c0mt00050g · Cited by 117 · see citing works
Regev‐Yochay, G., Trzciński, K., Thompson, C. M., Lipsitch, M., & Malley, R. (2007) · Journal of Bacteriology · doi:10.1128/jb.00813-07 · Cited by 107 · see citing works
A new structural paradigm in copper resistance in Streptococcus pneumoniae
Fu, Y., Tsui, H.-C. T., Bruce, K. E., Sham, L.-T., Higgins, K. A., Lisher, J. P., Kazmierczak, K. M., Maroney, M. J., Dann, C. E., Winkler, M. E., et al. (2013) · Nature Chemical Biology · doi:10.1038/nchembio.1168 · Cited by 93 · see citing works
Calcium efflux is essential for bacterial survival in the eukaryotic host
Rosch, J. W., Sublett, J. E., Gao, G., Wang, Y., & TUOMANEN, E. I. (2008) · Molecular Microbiology · doi:10.1111/j.1365-2958.2008.06425.x · Cited by 90 · see citing works
Self-citationThe Copper-Responsive RicR Regulon Contributes to Mycobacterium tuberculosis Virulence
Shi, X., Festa, R. A., Ioerger, T. R., Butler‐Wu, S. M., Sacchettini, J. C., Darwin, K. H., & Samanovic, M. I. (2014) · mBio · doi:10.1128/mbio.00876-13 · Cited by 86 · see citing works
Banci, L., Bertini, I., Ciofi-Baffoni, S., Del Conte, R., & Gonnelli, L. (2003) · Biochemistry · doi:10.1021/bi027096p · Cited by 85 · see citing works
The roles of transition metals in the physiology and pathogenesis of Streptococcus pneumoniae
Honsa, E. S., Johnson, M. D. L., & Rosch, J. W. (2013) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2013.00092 · Cited by 69 · see citing works
Self-citationKhalfaoui-Hassani, B., Astier, C., Nitschke, W., & Ouchane, S. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.116020 · Cited by 67 · see citing works
The immune system as a physiological indicator ofmarginal copper status?
O’Connor, J. M., HANNIGAN, B. M., Strain, J. J., & Bonham, M. P. (2002) · British Journal Of Nutrition · doi:10.1079/bjnbjn2002558 · Cited by 66 · see citing works
CopY-like Copper Inducible Repressors are Putative ‘Winged Helix’ Proteins
Portmann, R., Poulsen, K. R., Wimmer, R., & Solioz, M. (2006) · BioMetals · doi:10.1007/s10534-005-5381-3 · Cited by 58 · see citing works
Völlmecke, C., Drees, S. L., Reimann, J., Albers, S., & Lübben, M. (2012) · Microbiology · doi:10.1099/mic.0.055905-0 · Cited by 56 · see citing works
The role of zinc in the interplay between pathogenic streptococci and their hosts
Shafeeq, S., Kuipers, O. P., & Kloosterman, T. G. (2013) · Molecular Microbiology · doi:10.1111/mmi.12256 · Cited by 50 · see citing works
Djoko, K. Y., Franiek, J. A., Edwards, J. L., Falsetta, M. L., Kidd, S. P., Potter, A. J., Chen, N. H., Apicella, M. A., Jennings, M. P., & McEwan, A. G. (2011) · Infection and Immunity · doi:10.1128/iai.06163-11 · Cited by 49 · see citing works
Structure and Cu(I)-binding properties of the N-terminal soluble domains of Bacillus subtilis CopA
Singleton, C., Banci, L., Ciofi‐Baffoni, S., Tenori, L., Kihlken, M. A., Boetzel, R., & Brun, N. E. L. (2008) · Biochemical Journal · doi:10.1042/bj20071620 · Cited by 36 · see citing works
Sun, K., Gan, Y. X., & Metzger, D. W. (2011) · Infection and Immunity · doi:10.1128/iai.01143-10 · Cited by 25 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The Role of Copper and Zinc Toxicity in Innate Immune Defense against Bacterial Pathogens
Djoko, K. Y., Ong, C.-L. Y., Walker, M. J., & McEwan, A. G. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.r115.647099 · Cited by 417 · see citing works
The Use of Copper as an Antimicrobial Agent in Health Care, Including Obstetrics and Gynecology
Arendsen, L. P., Thakar, R., & Sultan, A. H. (2019) · Clinical Microbiology Reviews · doi:10.1128/cmr.00125-18 · Cited by 225 · see citing works
Copper tolerance in bacteria requires the activation of multiple accessory pathways
Giachino, A., & Waldron, K. J. (2020) · Molecular Microbiology · doi:10.1111/mmi.14522 · Cited by 223 · see citing works
The Yin and Yang of copper during infection
Besold, A. N., Culbertson, E. M., & Culotta, V. C. (2016) · JBIC Journal of Biological Inorganic Chemistry · doi:10.1007/s00775-016-1335-1 · Cited by 215 · see citing works
The Impact of Dietary Transition Metals on Host-Bacterial Interactions
Lopez, C. A., & Skaar, E. P. (2018) · Cell Host & Microbe · doi:10.1016/j.chom.2018.05.008 · Cited by 190 · see citing works
“In response, bacteria have evolved mechanisms to relieve hostmediated copper stress including copper exporters (Johnson et al., 2015).”
BackgroundCopper signaling in the brain and beyond
Ackerman, C. M., & Chang, C. J. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r117.000176 · Cited by 170 · see citing works
Cu Homeostasis in Bacteria: The Ins and Outs
Andrei, A., Öztürk, Y., Khalfaoui-Hassani, B., Rauch, J., Marckmann, D., Trasnea, P.-I., Daldal, F., & Koch, H.-G. (2020) · Membranes · doi:10.3390/membranes10090242 · Cited by 153 · see citing works
Metals as phagocyte antimicrobial effectors
Sheldon, J. R., & Skaar, E. P. (2019) · Current Opinion in Immunology · doi:10.1016/j.coi.2019.04.002 · Cited by 143 · see citing works
Relationship between copper and immunity: The potential role of copper in tumor immunity
Cheng, F., Peng, G., Lu, Y., Wang, K., Ju, Q., Ju, Y., & Ouyang, M. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1019153 · Cited by 124 · see citing works
Focarelli, F., Giachino, A., & Waldron, K. J. (2022) · PLoS Pathogens · doi:10.1371/journal.ppat.1010617 · Cited by 97 · see citing works
Healy, C. M., Muñoz‐Wolf, N., Strydom, J., Faherty, L., Williams, N. C., Kenny, S., Donnelly, S. C., & Cloonan, S. M. (2021) · Respiratory Research · doi:10.1186/s12931-021-01722-y · Cited by 89 · see citing works
Copper stress in Staphylococcus aureus leads to adaptive changes in central carbon metabolism
Tarrant, E., Riboldi, G. P., McIlvin, M. R., Stevenson, J. A., Barwinska‐Sendra, A., Stewart, L. J., Saito, M. A., & Waldron, K. J. (2018) · Metallomics · doi:10.1039/c8mt00239h · Cited by 82 · see citing works
Role of Glutathione in Buffering Excess Intracellular Copper in <i>Streptococcus pyogenes</i>
Stewart, L. J., Ong, C.-L. Y., Zhang, M. M., Brouwer, S., McIntyre, L., Davies, M. R., Walker, M. J., McEwan, A. G., Waldron, K. J., & Djoko, K. Y. (2020) · mBio · doi:10.1128/mbio.02804-20 · Cited by 72 · see citing works
Hyre, A., Casanova-Hampton, K., & Subashchandrabose, S. (2021) · EcoSal Plus · doi:10.1128/ecosalplus.esp-0014-2020 · Cited by 67 · see citing works
Ladomersky, E., Khan, A. A., Shanbhag, V., Cavet, J. S., Chan, J., Weisman, G. A., & Petris, M. J. (2017) · Infection and Immunity · doi:10.1128/iai.00351-17 · Cited by 64 · see citing works
Hyre, A. N., Kavanagh, K., Kock, N. D., Donati, G. L., & Subashchandrabose, S. (2016) · Infection and Immunity · doi:10.1128/iai.01041-16 · Cited by 62 · see citing works
Purves, J., Thomas, J., Riboldi, G. P., Zapotoczna, M., Tarrant, E., Andrew, P. W., Londoño, A., Planet, P. J., Geoghegan, J. A., Waldron, K. J., et al. (2018) · Environmental Microbiology · doi:10.1111/1462-2920.14088 · Cited by 61 · see citing works
Characterization of Acinetobacter baumannii Copper Resistance Reveals a Role in Virulence
Williams, C. L., Neu, H. M., Alamneh, Y. A., Reddinger, R. M., Jacobs, A. C., Singh, S., Abu-Taleb, R., Michel, S. L. J., Zurawski, D. V., & Merrell, D. S. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.00016 · Cited by 58 · see citing works
Zapotoczna, M., Riboldi, G. P., Moustafa, A. M., Dickson, E. M., Narechania, A., Morrissey, J. A., Planet, P. J., Holden, M. T. G., Waldron, K. J., & Geoghegan, J. A. (2018) · mBio · doi:10.1128/mbio.00550-18 · Cited by 53 · see citing works
Arachidonic Acid Stress Impacts Pneumococcal Fatty Acid Homeostasis
Eijkelkamp, B. A., Neville, S. L., Pederick, V. G., Trappetti, C., Gregory, M. K., Whittall, J. J., Paton, J. C., & McDevitt, C. A. (2018) · Frontiers in Microbiology · doi:10.3389/fmicb.2018.00813 · Cited by 45 · see citing works
Kumar, P. K., Tomo, S., Purohit, P., Sankanagoudar, S., Charan, J., Purohit, A. H. L., Nag, V., Bhatia, P. K., Singh, K., Dutt, N., et al. (2022) · Biological Trace Element Research · doi:10.1007/s12011-022-03124-7 · Cited by 41 · see citing works
Copper as a potential adjunct therapy for critically ill COVID-19 patients
Fooladi, S., Matin, S., & Mahmoodpoor, A. (2020) · Clinical Nutrition ESPEN · doi:10.1016/j.clnesp.2020.09.022 · Cited by 39 · see citing works
Metalloregulation of Helicobacter pylori physiology and pathogenesis
Haley, K. P., & Gaddy, J. A. (2015) · Frontiers in Microbiology · doi:10.3389/fmicb.2015.00911 · Cited by 37 · see citing works
Competition for Manganese at the Host–Pathogen Interface
Kelliher, J. L., & Kehl-Fie, T. E. (2016) · Progress in Molecular Biology and Translational Science · doi:10.1016/bs.pmbts.2016.05.002 · Cited by 34 · see citing works
Self-citationPhysiological roles of bacillithiol in intracellular metal processing
Rosario-Cruz, Z., & Boyd, J. M. (2016) · Current Genetics · doi:10.1007/s00294-015-0511-0 · Cited by 34 · see citing works
Transition Metal Homeostasis in Streptococcus pyogenes and Streptococcus pneumoniae
Turner, A. G., Ong, C. Y., Walker, M. J., Djoko, K. Y., & McEwan, A. G. (2017) · Advances in microbial physiology/Advances in Microbial Physiology · doi:10.1016/bs.ampbs.2017.01.002 · Cited by 34 · see citing works
Copper in infectious disease: Using both sides of the penny
Culbertson, E. M., & Culotta, V. (2021) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2020.12.003 · Cited by 35 · see citing works
Dalecki, A. G., Zorn, K. M., Clark, A. M., Ekins, S., Narmore, W. T., Tower, N. A., Rasmussen, L. A., Bostwick, R. J., Kutsch, O., & Wolschendorf, F. (2019) · Metallomics · doi:10.1039/c8mt00342d · Cited by 30 · see citing works
Neville, S. L., Eijkelkamp, B. A., Lothian, A., Paton, J. C., Roberts, B. R., Rosch, J. W., & McDevitt, C. A. (2020) · Communications Biology · doi:10.1038/s42003-020-01417-y · Cited by 30 · see citing works
Self-citationSaenkham, P., Hyre, A. N., Hanson, B. S., Donati, G. L., Adams, L. G., Ryan, C., Londoño, A., Moustafa, A. M., Planet, P. J., & Subashchandrabose, S. (2021) · mBio · doi:10.1128/mbio.02038-21 · Cited by 30 · see citing works
Copper homeostasis dysregulation in respiratory diseases: a review of current knowledge
Song, W., Yue, Y., Zhang, Q., & Wang, X. (2024) · Frontiers in Physiology · doi:10.3389/fphys.2024.1243629 · Cited by 29 · see citing works
Copper Chaperone CupA and Zinc Control CopY Regulation of the Pneumococcal cop Operon
Neubert, M. J., Dahlmann, E. A., Ambrose, A. J., & Johnson, M. D. L. (2017) · mSphere · doi:10.1128/msphere.00372-17 · Cited by 29 · see citing works
Self-citationSynthetic biology approaches to copper remediation: bioleaching, accumulation and recycling
Giachino, A., Focarelli, F., Marles‐Wright, J., & Waldron, K. J. (2020) · FEMS Microbiology Ecology · doi:10.1093/femsec/fiaa249 · Cited by 27 · see citing works
P-type transport ATPases inLeishmaniaandTrypanosoma
Meade, J. C. (2019) · Parasite · doi:10.1051/parasite/2019069 · Cited by 26 · see citing works
Turner, A. G., Ong, C. Y., Djoko, K. Y., West, N. P., Davies, M. R., McEwan, A. G., & Walker, M. J. (2017) · Infection and Immunity · doi:10.1128/iai.00140-17 · Cited by 26 · see citing works
Huang, M. N., Liu, M., Liu, J., Zhu, D., Tang, Q., Jia, R., Chen, S., Zhao, X., Yang, Q., Wu, Y., et al. (2021) · Veterinary Research · doi:10.1186/s13567-021-00919-9 · Cited by 25 · see citing works
The S2 Cu( i ) site in CupA from Streptococcus pneumoniae is required for cellular copper resistance
Fu, Y., Bruce, K. E., Wu, H., & Giedroc, D. P. (2015) · Metallomics · doi:10.1039/c5mt00221d · Cited by 22 · see citing works
Tang, L., Huang, K., Xie, J., Yu, D., Sun, L., Huang, Q., & Bi, Y. (2017) · Aquaculture Nutrition · doi:10.1111/anu.12468 · Cited by 21 · see citing works
Fenlon, L. A., & Slauch, J. M. (2017) · Journal of Bacteriology · doi:10.1128/jb.00437-17 · Cited by 21 · see citing works
Sullivan, M. J., Goh, K. G. K., Gosling, D., Katupitiya, L., & Ulett, G. C. (2021) · Journal of Bacteriology · doi:10.1128/jb.00315-21 · Cited by 20 · see citing works
Zhou, Y., & Zhang, L. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1267931 · Cited by 20 · see citing works
Young, C., Gordon, L. D., Fang, Z., Holder, R. C., & Reid, S. D. (2015) · Journal of Bacteriology · doi:10.1128/jb.00127-15 · Cited by 20 · see citing works
Dalecki, A. G., Malalasekera, A. P., Schaaf, K., Kutsch, O., Bossmann, S. H., & Wolschendorf, F. (2016) · Metallomics · doi:10.1039/c6mt00003g · Cited by 20 · see citing works
Mutations in troABCD against Copper Overload in a copA Mutant of Streptococcus suis
Yang, X., Peng, W., Wang, Y., Yan, K., Liu, Z., Gao, T., Yang, K., Liu, W., Guo, R., Li, C., et al. (2022) · Applied and Environmental Microbiology · doi:10.1128/aem.01841-22 · Cited by 19 · see citing works
Burcham, L. R., Akbari, M. S., Alhajjar, N., Keogh, R. A., Radin, J. N., Kehl‐Fie, T. E., Belew, A. T., El-Sayed, N. M., McIver, K. S., & Doran, K. S. (2022) · mBio · doi:10.1128/mbio.00985-22 · Cited by 18 · see citing works
Self-citationMenghani, S. V., Rivera, A., Neubert, M. J., Hagerty, J. R., Lewis, L., Galgiani, J. N., Jolly, E. R., Alvin, J. W., & Johnson, M. D. L. (2021) · Microbiology Spectrum · doi:10.1128/spectrum.00778-21 · Cited by 17 · see citing works
Self-citationMetal Homeostasis in Pathogenic Streptococci
Akbari, M. S., Doran, K. S., & Burcham, L. R. (2022) · Microorganisms · doi:10.3390/microorganisms10081501 · Cited by 17 · see citing works
Kaur, I., Purves, J., Harwood, M., Ketley, J. M., Andrew, P. W., Waldron, K. J., & Morrissey, J. A. (2022) · Microbiology · doi:10.1099/mic.0.001162 · Cited by 16 · see citing works
O’Brien, H., Alvin, J. W., Menghani, S. V., Sanchez-Rosario, Y., Doorslaer, K. V., & Johnson, M. D. L. (2020) · mSphere · doi:10.1128/msphere.00411-20 · Cited by 16 · see citing works
Self-citationTotten, A. H., Crawford, C. L., Dalecki, A. G., Xiao, L., Wolschendorf, F., & Atkinson, T. P. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.01720 · Cited by 15 · see citing works
Yang, X.-Y., Li, N., Xu, J., Sun, X., & He, Q. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.01769 · Cited by 14 · see citing works
Kelley, B. R., Lu, J., Haley, K. P., Gaddy, J. A., & Johnson, J. G. (2020) · Metallomics · doi:10.1093/mtomcs/mfaa002 · Cited by 13 · see citing works
Crawford, C. L., Dalecki, A. G., Narmore, W. T., Hoff, J. S., Hargett, A. A., Renfrow, M. B., Zhang, M., Kalubowilage, M., Bossmann, S. H., Queern, S. L., et al. (2019) · Metallomics · doi:10.1039/c8mt00316e · Cited by 12 · see citing works
Determinants of bacterial survival and proliferation in blood
Lê-Bury, P., Echenique-Rivera, H., Pizarro‐Cerdá, J., & Dussurget, O. (2024) · FEMS Microbiology Reviews · doi:10.1093/femsre/fuae013 · Cited by 11 · see citing works
Low copper availability limits Helicobacter infection in mice
Esposito, R., Vllahu, M., Morello, S., Baldantoni, D., Bellino, A., Petrella, A., Eletto, D., Porta, A., & Tosco, A. (2019) · FEBS Journal · doi:10.1111/febs.15188 · Cited by 11 · see citing works
Improved diagnostic markers for invasive pulmonary aspergillosis in COPD patients
Long, Z., Li, X., Li, Z., Hu, J., Qiu, Y., Li, S., Zhan, Y., Ye, F., & Wang, Y. (2024) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2024.1294971 · Cited by 9 · see citing works
Menghani, S. V., Cutcliffe, M. P., Sanchez-Rosario, Y., Pok, C., Watson, A., Neubert, M. J., Ochoa, K., Wu, H.-J. J., & Johnson, M. D. L. (2022) · Infection and Immunity · doi:10.1128/iai.00597-21 · Cited by 8 · see citing works
Self-citationThe role of CopA in Streptococcus pyogenes copper homeostasis and virulence
Dao, T. H., Iverson, A., Neville, S. L., Johnson, M. D. L., McDevitt, C. A., & Rosch, J. W. (2023) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2023.112122 · Cited by 7 · see citing works
Self-citationTranscriptomic analysis of Streptococcus agalactiae periprosthetic joint infection
Cho, H., Masters, T. L., Greenwood‐Quaintance, K. E., Johnson, S. P., Jeraldo, P., Chia, N., Pu, M., Abdel, M. P., & Patel, R. (2021) · MicrobiologyOpen · doi:10.1002/mbo3.1256 · Cited by 7 · see citing works
Host-Mediated Copper Stress Is Not Protective against Streptococcus pneumoniae D39 Infection
Neville, S. L., Cunningham, B. A., Maunders, E. A., Tan, A., Watts, J. A., Ganio, K., Eijkelkamp, B. A., Pederick, V. G., de Vega, R. G., Clases, D., et al. (2022) · Microbiology Spectrum · doi:10.1128/spectrum.02495-22 · Cited by 7 · see citing works
Wong, S. M. S., Gawronski, J. D., & Akerley, B. J. (2023) · Infection and Immunity · doi:10.1128/iai.00091-23 · Cited by 7 · see citing works
CopA Protects Actinobacillus pleuropneumoniae against Copper Toxicity
Peng, W., Yang, X., Yan, K., Chen, H., Yuan, F., & Bei, W. (2021) · Veterinary Microbiology · doi:10.1016/j.vetmic.2021.109122 · Cited by 6 · see citing works
A critical role of copper homeostasis in the virulence of Klebsiella pneumoniae
Han, M., Chen, Q., Xu, F., Zhao, C., Ma, X., Jin, Q., Yang, J. F., Wang, Y., Qiang, R., Hong, D., et al. (2025) · Communications Biology · doi:10.1038/s42003-025-09002-x · Cited by 5 · see citing works
AL-Jabri, Z., Al-Shabibi, Z., Al-Bimani, A., Al-Hinai, A., Shabibi, A. A., & Rizvi, M. (2021) · Microorganisms · doi:10.3390/microorganisms9091824 · Cited by 5 · see citing works
Effluxosomes and the evolution of metal resistance in Mycobacterium tuberculosis
Benastre, L., Dupuy, P., Gutierrez, C., Demange, P., & Neyrolles, O. (2026) · Infection and Immunity · doi:10.1128/iai.00307-26 · Cited by 3 · see citing works
Roop, R. M., Baumgartner, J. E., Pitzer, J. E., & Martin, D. W. (2017) · Springer eBooks · doi:10.1007/978-3-319-53622-4_6 · Cited by 3 · see citing works
Spatial distribution of trace metals and associated transport proteins during bacterial infection
de Vega, R. G., Clases, D., Cunningham, B. A., Ganio, K., Neville, S. L., McDevitt, C. A., & Doble, P. (2023) · Analytical and Bioanalytical Chemistry · doi:10.1007/s00216-023-05068-w · Cited by 3 · see citing works
Nyazika, T. K., Sibale, L., Phiri, J., Croix, M. D. S., Jasiunaite, Z., Mkandawire, C., Malamba, R., Kankwatira, A., Manduwa, M., Ferreira, D. M., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.992659 · Cited by 3 · see citing works
Definition of the effector landscape across 13 phytoplasma proteomes with LEAPH and EffectorComb
Calia, G., Cestaro, A., Schuler, H., Janik, K., Donati, C., Moser, M., & Bottini, S. (2024) · NAR Genomics and Bioinformatics · doi:10.1093/nargab/lqae087 · Cited by 2 · see citing works
Copper homeostasis in Streptococcus and Neisseria: Known knowns and unknown knowns
Howell, A., Chogule, S., & Djoko, K. Y. (2025) · Advances in microbial physiology/Advances in Microbial Physiology · doi:10.1016/bs.ampbs.2024.11.001 · Cited by 2 · see citing works
Yang, R., Han, S., Yu, Y., Li, H., Helmann, J. D., Schaufler, K., Johnson, M. D. L., Yang, Q., & Rensing, C. (2025) · Microbiology Spectrum · doi:10.1128/spectrum.02634-24 · Cited by 2 · see citing works
Self-citationTargeting cu metabolism as a potential therapeutic strategy for pulmonary fibrosis
Li, B., Zhang, M., Cai, J., Li, N. S., Li, X.-H., & Cheng, H. (2025) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2025.189379 · Cited by 2 · see citing works
Sullivan, M. J., Goh, K. G. K., Gosling, D., Katupitiya, L., & Ulett, G. C. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.03.25.437115 · Cited by 2 · see citing works
Copper homeostasis dysregulation and cuproptosis in respiratory diseases
Gao, Y., Chen, X., & Xu, Y. (2026) · Experimental Lung Research · doi:10.1080/01902148.2026.2649073 · Cited by 1 · see citing works
Copper Metabolism in Isolated Macrophages: Regulator of Immunity and Inflammation
Leng, X., Yu, P., Xu, Z., Xia, C., Du, R., Luo, Q., Zhu, Y., & Guo, H. (2026) · Veterinary Sciences · doi:10.3390/vetsci13060511 · Cited by 1 · see citing works
Iron and its import systems enhance copper accumulation in Streptococcus pneumoniae
Sanchez-Rosario, Y., Durckel, M., Meas, R., Rohilla, M., Parate, S., Senanayaka, S. G. M. S. D., Ibarra, J. A. C., Wierzbicki, I. H., Gonzalez, D. J., & Johnson, M. D. L. (2026) · mSphere · doi:10.1128/msphere.00165-26 · Cited by 1 · see citing works
Self-citationBiological links between nanoparticle biosynthesis and stress responses in bacteria
Chen, A., Keitz, B. K., & Contreras, L. M. (2018) · Mexican Journal of Biotechnology · doi:10.29267/mxjb.2018.3.4.44 · Cited by 1 · see citing works
Characterization of consensus operator site for Streptococcus pneumoniae copper repressor, CopYPreprint
O’Brien, H., Alvin, J. W., Menghani, S. V., Doorslaer, K. V., & Johnson, M. D. L. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/676700 · Cited by 1 · see citing works
Self-citationHuang, M., Liu, M., Liu, J., Zhu, D., Tang, Q., Jia, R., Chen, S., Zhao, X., Yang, Q., Wu, Y., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14251990
Huang, M., Liu, M., Liu, J., Zhu, D., Tang, Q., Jia, R., Chen, S., Zhao, X., Yang, Q., Wu, Y., et al. (2021) · Figshare · doi:10.6084/m9.figshare.14251993
Panda, L., Halder, A., Sk, S., Gupta, M., C., S., Shashikala Reddy, P., Barpanda, A., & Prashanth, K. (2026) · Journal of Proteome Research · doi:10.1021/acs.jproteome.5c00693
Huang, S., & Song, Y. (2026) · Open Medicine · doi:10.1515/med-2026-1415
Unveiling the role of abnormal copper metabolism in systemic lupus erythematosus
Chen, Z., Yan, S., Deng, C., Wang, W., Guo, Y., Deng, S., Lü, D., Peng, L., Zhang, W., Li, M., et al. (2026) · Journal of Autoimmunity · doi:10.1016/j.jaut.2026.103614
CopY as a Transcriptional Duet Orchestrating Copper Homeostasis via Asymmetry-Dependent DNA AffinityPreprint
Hirsch, M., Benny, A. L., Hofmann, L., Shenberger, Y., Gevorkyan‐Airapetov, L., Saxena, S., & Ruthstein, S. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.30.755846
- Authors
- Johnson, M. D. L., Kehl-Fie, T. E., Klein, R., Kelly, J., Burnham, C., Mann, B., & Rosch, J. W.
- Affiliations
- St. Jude Children's Research Hospital (US)
- University of Illinois Urbana-Champaign, Department of Microbiology, Urbana, Illinois, USA
- Venue
- Infection and Immunity
- Publisher
- American Society for Microbiology
- Published
- 2015-04
- Volume
- 83
- Issue
- 4
- Pages
- 1684-1694
- ISSN
- 0019-9567 (ISSN-L)
- 1098-5522
- PMC
- PMC4363445
- OpenAlex
- W2051144562
- Cited by
- 84
- References
- 52
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 4 · 2023: 4 · 2022: 10 · 2021: 13 · 2020: 9 · 2019: 9 · 2018: 6 · 2017: 8 · 2016: 4 · 2015: 5
- FWCI
- 5.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Infection and Immunity (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Funders
- American Lebanese Syrian Associated Charities
- National Heart, Lung, and Blood Institute (T32HL094296)
- National Cancer Institute (5R25 CA 23944, R25CA023944)
- National Institute of Allergy and Infectious Diseases (R01AI110618, K22AI104805)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Health Sciences › Medicine › Epidemiology › Pneumonia and Respiratory Infections
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- copper efflux, Streptococcus pneumoniae, COPA, copper homeostasis, copper stress, bacterial virulence, immune evasion, pulmonary infection, trace metal homeostasis
- MeSH terms
- Animals, Bacterial Adhesion, Bacterial Proteins, Cell Line, Copper, Humans, Lung, Macrophages, Mice, Inbred BALB C, Pneumococcal Infections, Streptococcus pneumoniae, Gene Expression Regulation, Bacterial, Bacteremia, Gene Deletion, Molecular Chaperones, Cation Transport Proteins, Mice
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
