Separable roles for Mycobacterium tuberculosis ESX-3 effectors in iron acquisition and virulence

Tufariello, JoAnn M.; Chapman, Jessica R.; Kerantzas, Christopher A.; Wong, Ka-Wing; Vilchèze, Catherine; Jones, Christopher M.; Cole, Laura E.; Tinaztepe, Emir; Thompson, Victor; Fenyö, David; Niederweis, Michael; Ueberheide, Beatrix; Philips, Jennifer A.; Jacobs, William R.

doi:10.1073/pnas.1523321113

Cited by 215Tuberculosis Research and EpidemiologyBacterial Genetics and BiotechnologyMycobacterium research and diagnosis

Separable roles for Mycobacterium tuberculosis ESX-3 effectors in iron acquisition and virulence

Open access

Tufariello, JoAnn M., Chapman, Jessica R., Kerantzas, Christopher A., Wong, Ka-Wing, Vilchèze, Catherine, Jones, Christopher M., Cole, Laura E., Tinaztepe, Emir +6 more·2016·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1523321113PMC PMC4725510

Open this paper in CoChat — free account

Abstract

Mycobacterium tuberculosis (Mtb) encodes five type VII secretion systems (T7SS), designated ESX-1-ESX-5, that are critical for growth and pathogenesis. The best characterized is ESX-1, which profoundly impacts host cell interactions. In contrast, the ESX-3 T7SS is implicated in metal homeostasis, but efforts to define its function have been limited by an inability to recover deletion mutants. We overcame this impediment using medium supplemented with various iron complexes to recover mutants with deletions encompassing select genes within esx-3 or the entire operon. The esx-3 mutants were defective in uptake of siderophore-bound iron and dramatically accumulated cell-associated mycobactin siderophores. Proteomic analyses of culture filtrate revealed that secretion of EsxG and EsxH was codependent and that EsxG-EsxH also facilitated secretion of several members of the proline-glutamic acid (PE) and proline-proline-glutamic acid (PPE) protein families (named for conserved PE and PPE N-terminal motifs). Substrates that depended on EsxG-EsxH for secretion included PE5, encoded within the esx-3 locus, and the evolutionarily related PE15-PPE20 encoded outside the esx-3 locus. In vivo characterization of the mutants unexpectedly showed that the ESX-3 secretion system plays both iron-dependent and -independent roles in Mtb pathogenesis. PE5-PPE4 was found to be critical for the siderophore-mediated iron-acquisition functions of ESX-3. The importance of this iron-acquisition function was dependent upon host genotype, suggesting a role for ESX-3 secretion in counteracting host defense mechanisms that restrict iron availability. Further, we demonstrate that the ESX-3 T7SS secretes certain effectors that are important for iron uptake while additional secreted effectors modulate virulence in an iron-independent fashion.

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

Crossref · 10.1073/pnas.1523321113

Cites

78 of 78 references verified0 citation errors · 0 not checkable

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?

ESX-3 is important for metal homeostasis, pathogenicity, and immunogenicity.
“ESX-3 is important for metal homeostasis, pathogenicity, and immunogenicity (29)(30)(31).”
From ESX/Type VII Secretion Systems—An Important Way Out for Mycobacterial Proteins (2019) · cites this paper as [31]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing
Benjamini, Y., & Hochberg, Y. (1995) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/j.2517-6161.1995.tb02031.x · Cited by 109,482 · see citing works
Accurate proteome-wide label-free quantification by delayed normalization and maximal peptide ratio extraction, termed MaxLFQ
Cox, J., Hein, M. Y., Luber, C. A., Paron, I., Nagaraj, N., & Mann, M. (2014) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m113.031591 · Cited by 5,180 · see citing works
New use of BCG for recombinant vaccines
Stover, C. K., de la Cruz, V. F., Fuerst, T. R., Burlein, J. E., Benson, L. A., Bennett, L. T., Bansal, G. P., Young, J. F., Lee, M., Hatfull, G. F., et al. (1991) · Nature · doi:10.1038/351456a0 · Cited by 1,492 · see citing works
Self-citation
Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling
Betts, J. C., Lukey, P. T., Robb, L. C., McAdam, R. A., & Duncan, K. (2002) · Molecular Microbiology · doi:10.1046/j.1365-2958.2002.02779.x · Cited by 1,395 · 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
Type VII secretion — mycobacteria show the way
Abdallah, A. M., Gey van Pittius, N. C., DiGiuseppe Champion, P. A., Cox, J., Luirink, J., Vandenbroucke-Grauls, C. M. J. E., Appelmelk, B. J., & Bitter, W. (2007) · Nature Reviews Microbiology · doi:10.1038/nrmicro1773 · Cited by 763 · see citing works
Variations in the NRAMP1 Gene and Susceptibility to Tuberculosis in West Africans
Bellamy, R., Ruwende, C., Corrah, T., McAdam, K. P. W. J., Whittle, H. C., & Hill, A. V. S. (1998) · New England Journal of Medicine · doi:10.1056/nejm199803053381002 · Cited by 731 · see citing works
The primary mechanism of attenuation of bacillus Calmette–Guérin is a loss of secreted lytic function required for invasion of lung interstitial tissue
Hsu, T., Hingley-Wilson, S. M., Chen, B., Chen, M., Dai, A. Z., Morin, P. M., Marks, C. B., Padiyar, J., Goulding, C., Gingery, M., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1635213100 · Cited by 731 · see citing works
Self-citation
Loss of RD1 contributed to the attenuation of the live tuberculosis vaccines Mycobacterium bovis BCG and Mycobacterium microti
Pym, A. S., Brodin, P., Brosch, R., Huerre, M., & Cole, S. T. (2002) · Molecular Microbiology · doi:10.1046/j.1365-2958.2002.03237.x · Cited by 729 · see citing works
The Ity/Lsh/Bcg locus: natural resistance to infection with intracellular parasites is abrogated by disruption of the Nramp1 gene
Vidal, S., Tremblay, M. L., Govoni, G., Gauthier, S., Sebastiani, G., Malo, D., Skamene, E., Olivier, M., Jothy, S., & Gros, P. (1995) · The Journal of experimental medicine · doi:10.1084/jem.182.3.655 · Cited by 603 · see citing works
Specialized transduction: an efficient method for generating marked and unmarked targeted gene disruptions in Mycobacterium tuberculosis, M. bovis BCG and M. smegmatis
Bardarov, S., Bardarov, S. S., Pavelka, M. S., Sambandamurthy, V. K., Larsen, M. H., Tufariello, J. M., Chan, J., Hatfull, G. F., & Jacobs, W. R. (2002) · Microbiology · doi:10.1099/00221287-148-10-3007 · Cited by 590 · see citing works
Self-citation
Deletion of RD1 fromMycobacterium tuberculosisMimics Bacille Calmette‐Guérin Attenuation
Lewis, K. N., Liao, R., Guinn, K. M., Hickey, M. J., Smith, S., Behr, M. A., & Sherman, D. R. (2003) · The Journal of Infectious Diseases · doi:10.1086/345862 · Cited by 588 · see citing works
Acute infection and macrophage subversion by Mycobacterium tuberculosis require a specialized secretion system
Stanley, S. A., Raghavan, S., Hwang, W. W., & Cox, J. S. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2235593100 · Cited by 570 · see citing works
The salicylate-derived mycobactin siderophores of Mycobacterium tuberculosis are essential for growth in macrophages
De Voss, J. J., Rutter, K., Schroeder, B. G., Su, H., Zhu, Y., & Barry, C. E. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.3.1252 · Cited by 532 · see citing works
ideR , an Essential Gene in Mycobacterium tuberculosis : Role of IdeR in Iron-Dependent Gene Expression, Iron Metabolism, and Oxidative Stress Response
Rodríguez, G. M., Voskuil, M. I., Gold, B., Schoolnik, G. K., & Smith, I. (2002) · Infection and Immunity · doi:10.1128/iai.70.7.3371-3381.2002 · Cited by 491 · see citing works
Differential regulation of iron homeostasis during human macrophage polarized activation
Recalcati, S., Locati, M., Marini, A., Santambrogio, P., Zaninotto, F., De Pizzol, M., Zammataro, L., Girelli, D., & Cairo, G. (2010) · European Journal of Immunology · doi:10.1002/eji.200939889 · Cited by 438 · see citing works
Divalent-metal transport by NRAMP proteins at the interface of host–pathogen interactions
Forbes, J. R., & Gros, P. (2001) · Trends in Microbiology · doi:10.1016/s0966-842x(01)02098-4 · Cited by 424 · see citing works
Evolution and expansion of the Mycobacterium tuberculosis PE and PPE multigene families and their association with the duplication of the ESAT-6 (esx) gene cluster regions.
van Pittius, N. C. G., Sampson, S. L., Lee, H., Kim, Y., van Helden, P. D., & Warren, R. M. (2006) · BMC Evolutionary Biology · doi:10.1186/1471-2148-6-95 · Cited by 423 · see citing works
Mutually dependent secretion of proteins required for mycobacterial virulence.
Fortune, S. M., Jaeger, A., Sarracino, D. A., Chase, M. R., Sassetti, C. M., Sherman, D. R., Bloom, B. R., & Rubin, E. J. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0504922102 · Cited by 396 · see citing works
Mycobacterial Esx-3 is required for mycobactin-mediated iron acquisition
Siegrist, M. S., Unnikrishnan, M., McConnell, M. J., Borowsky, M. L., Cheng, T., Siddiqi, N., Fortune, S. M., Moody, D. B., & Rubin, E. J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900589106 · Cited by 329 · see citing works
Comprehensive analysis of exported proteins from Mycobacterium tuberculosis H37Rv
Målen, H., Berven, F. S., Fladmark, K. E., & Wiker, H. G. (2007) · PROTEOMICS · doi:10.1002/pmic.200600853 · Cited by 314 · see citing works
Dissection of ESAT-6 System 1 of Mycobacterium tuberculosis and Impact on Immunogenicity and Virulence
Brodin, P. M., Majlessi, L., Marsollier, L., de Jonge, M. I., Bottai, D., Demangel, C., Hinds, J., Neyrolles, O., Butcher, P. D., Leclerc, C., et al. (2005) · Infection and Immunity · doi:10.1128/iai.74.1.88-98.2006 · Cited by 312 · see citing works
Systematic Genetic Nomenclature for Type VII Secretion Systems
Bitter, W., Houben, E. N. G., Bottai, D., Brodin, P., Brown, E. J., Cox, J. S., Derbyshire, K., Fortune, S. M., Gao, L.-Y., Liu, J., et al. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000507 · Cited by 307 · see citing works
Polarization dictates iron handling by inflammatory and alternatively activated macrophages
Corna, G., Campana, L., Pignatti, E., Castiglioni, A., Tagliafico, E., Bosurgi, L., Campanella, A., Brunelli, S., Manfredi, A. A., Apostoli, P., et al. (2010) · Haematologica · doi:10.3324/haematol.2010.023879 · Cited by 304 · see citing works
PPE and PE_PGRS proteins of Mycobacterium marinum are transported via the type VII secretion system ESX‐5
Abdallah, A. M., Verboom, T., Weerdenburg, E. M., van Pittius, N. C. G., Mahasha, P. W., Jiménez, C. R., Parra, M., Cadieux, N., Brennan, M. J., Appelmelk, B. J., et al. (2009) · Molecular Microbiology · doi:10.1111/j.1365-2958.2009.06783.x · Cited by 268 · see citing works
Discovery of a Siderophore Export System Essential for Virulence of Mycobacterium tuberculosis
Wells, R. M., Jones, C. M., Xi, Z., Speer, A., Danilchanka, O., Doornbos, K. S., Sun, P., Wu, F., Tian, C., & Niederweis, M. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003120 · Cited by 267 · see citing works
Self-citation
Haplotype Mapping and Sequence Analysis of the Mouse Nramp Gene Predict Susceptibility to Infection with Intracellular Parasites
Malo, D., Vogan, K. J., Vidal, S. M., Hu, J., Cellier, M. F., Schurr, E., Fuks, A., Bumstead, N., Morgan, K. W., & Gros, P. (1994) · Genomics · doi:10.1006/geno.1994.1458 · Cited by 259 · see citing works
Global Analysis of theMycobacterium tuberculosisZur (FurB) Regulon
Maciag, A. E., Dainese, E., Rodríguez, G. M., Milano, A., Provvedi, R., Pasca, M. R., Smith, I., Palù, G., Riccardi, G., & Manganelli, R. (2006) · Journal of Bacteriology · doi:10.1128/jb.01190-06 · Cited by 257 · see citing works
ESX/type VII secretion systems and their role in host–pathogen interaction
Siméone, R., Bottai, D., & Brosch, R. (2009) · Current Opinion in Microbiology · doi:10.1016/j.mib.2008.11.003 · Cited by 250 · see citing works
Take five — Type VII secretion systems of Mycobacteria
Houben, E. N. G., Korotkov, K. V., & Bitter, W. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.11.003 · Cited by 223 · see citing works
Mycobacteria, metals, and the macrophage
Neyrolles, O., Wolschendorf, F., Mitra, A., & Niederweis, M. (2015) · Immunological Reviews · doi:10.1111/imr.12265 · Cited by 217 · see citing works
Self-citation
Interleukin-10 Promotes Mycobacterium tuberculosis Disease Progression in CBA/J Mice
Beamer, G., Flaherty, D. K., Assogba, B. D., Stromberg, P. C., Juarrero, M. G., Malefyt, R. D. W., Vesosky, B., & Turner, J. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.8.5545 · Cited by 216 · see citing works
Mycobacterium tuberculosis ΔRD1 ΔpanCD: A safe and limited replicating mutant strain that protects immunocompetent and immunocompromised mice against experimental tuberculosis
Sambandamurthy, V. K., Derrick, S. C., Hsu, T., Chen, B., Larsen, M. H., Jalapathy, K. V., Chen, M., Kim, J., Porcelli, S. A., Chan, J., et al. (2006) · Vaccine · doi:10.1016/j.vaccine.2006.05.097 · Cited by 213 · see citing works
Self-citation
Disruption of the ESX‐5 system of Mycobacterium tuberculosis causes loss of PPE protein secretion, reduction of cell wall integrity and strong attenuation
Bottai, D., Di Luca, M., Majlessi, L., Frigui, W., Simeone, R., Sayes, F., Bitter, W., Brennan, M. J., Leclerc, C., Batoni, G., et al. (2012) · Molecular Microbiology · doi:10.1111/j.1365-2958.2012.08001.x · Cited by 210 · see citing works
Role for Mycobacterium tuberculosis Membrane Vesicles in Iron Acquisition
Prados‐Rosales, R., Weinrick, B. C., Piqué, D. G., Jacobs, W. R., Casadevall, A., & Rodríguez, G. M. (2014) · Journal of Bacteriology · doi:10.1128/jb.01090-13 · Cited by 209 · see citing works
Self-citation
A recombinant Mycobacterium smegmatis induces potent bactericidal immunity against Mycobacterium tuberculosis
Sweeney, K. A., Dao, D. N., Goldberg, M. F., Hsu, T., Venkataswamy, M. M., Henao-Tamayo, M. I., Ordway, D. J., Sellers, R. S., Jain, P., Chen, B., et al. (2011) · Nature Medicine · doi:10.1038/nm.2420 · Cited by 208 · see citing works
Self-citation
Heme Oxygenase-1 expression in M-CSF-polarized M2 macrophages contributes to LPS-induced IL-10 release
Sierra‐Filardi, E., Vega, M. A., Sánchez‐Mateos, P., Corbí, A. L., & Puig‐Kröger, A. (2010) · Immunobiology · doi:10.1016/j.imbio.2010.05.020 · Cited by 204 · see citing works
Discovery and characterization of a unique mycobacterial heme acquisition system
Tullius, M. V., Harmston, C. A., Owens, C. P., Chim, N., Morse, R. P., McMath, L. M., Iniguez, A., Kimmey, J. M., Sawaya, M. R., Whitelegge, J. P., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1009516108 · Cited by 199 · see citing works
Characterization of aMycobacterium tuberculosisESX-3 Conditional Mutant: Essentiality and Rescue by Iron and Zinc
Serafini, A., Boldrin, F., Palù, G., & Manganelli, R. (2009) · Journal of Bacteriology · doi:10.1128/jb.00756-09 · Cited by 198 · see citing works
General secretion signal for the mycobacterial type VII secretion pathway
Daleke, M. H., Ummels, R., Bawono, P., Heringa, J., Vandenbroucke‐Grauls, C. M. J. E., Luirink, J., & Bitter, W. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1119453109 · Cited by 192 · see citing works
Mycobacterium tuberculosis Type VII Secreted Effector EsxH Targets Host ESCRT to Impair Trafficking
Mehra, A., Zahra, A., Thompson, V., Sirisaengtaksin, N., Wells, A., Porto, M., Köster, S., Penberthy, K., Kubota, Y., Dricot, A., et al. (2013) · PLoS Pathogens · doi:10.1371/journal.ppat.1003734 · Cited by 192 · see citing works
Self-citation
Genetic Manipulation of Mycobacterium tuberculosis
Larsen, M. H., Biermann, K., Tandberg, S., Hsu, T., & Jacobs, W. R. (2007) · Current Protocols in Microbiology · doi:10.1002/9780471729259.mc10a02s6 · Cited by 189 · see citing works
Self-citation
Specialized Transduction Designed for Precise High-Throughput Unmarked Deletions in Mycobacterium tuberculosis
Jain, P., Hsu, T., Arai, M., Biermann, K., Thaler, D. S., Nguyen, A., González, P. A., Tufariello, J. M., Kriakov, J., Chen, B., et al. (2014) · mBio · doi:10.1128/mbio.01245-14 · Cited by 175 · see citing works
Self-citation
Epitope Mapping of the Immunodominant Antigen TB10.4 and the Two Homologous Proteins TB10.3 and TB12.9, Which Constitute a Subfamily of the esat-6 Gene Family
Skjøt, R. L. V., Brock, I., Arend, S. M., Munk, M. E., Theisen, M., Ottenhoff, T. H. M., & Andersen, P. L. (2002) · Infection and Immunity · doi:10.1128/iai.70.10.5446-5453.2002 · Cited by 169 · see citing works
Composition of the type <scp>VII</scp> secretion system membrane complex
Houben, E. N. G., Bestebroer, J., Ummels, R., Wilson, L., Piersma, S. R., Jiménez, C. R., Ottenhoff, T. H. M., Luirink, J., & Bitter, W. (2012) · Molecular Microbiology · doi:10.1111/j.1365-2958.2012.08206.x · Cited by 168 · see citing works
Mycobacterium tuberculosis Exploits Human Interferon γ to Stimulate Macrophage Extracellular Trap Formation and Necrosis
Wong, K., & Jacobs, W. R. (2013) · The Journal of Infectious Diseases · doi:10.1093/infdis/jit097 · Cited by 143 · see citing works
Self-citation
Protein secretion systems in Mycobacteria
Champion, P. A. D., & Cox, J. S. (2007) · Cellular Microbiology · doi:10.1111/j.1462-5822.2007.00943.x · Cited by 142 · see citing works
Substrates Control Multimerization and Activation of the Multi-Domain ATPase Motor of Type VII Secretion
Rosenberg, O. S., Dovala, D., Li, X., Connolly, L., Bendebury, A., Finer-Moore, J., Holton, J., Cheng, Y., Stroud, R. M., & Cox, J. S. (2015) · Cell · doi:10.1016/j.cell.2015.03.040 · Cited by 134 · see citing works
Disruption of Mycobactin Biosynthesis Leads to Attenuation of Mycobacterium tuberculosis for Growth and Virulence
Reddy, P. V., Puri, R. V., Chauhan, P., Kar, R., Rohilla, A., Khera, A., & Tyagi, A. K. (2013) · The Journal of Infectious Diseases · doi:10.1093/infdis/jit250 · Cited by 127 · see citing works
Self-poisoning of Mycobacterium tuberculosis by interrupting siderophore recycling
Jones, C. M., Wells, R. M., Madduri, A. V. R., Renfrow, M. B., Ratledge, C., Moody, D. B., & Niederweis, M. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1311402111 · Cited by 125 · see citing works
Self-citation
Structure of a PE–PPE–EspG complex from Mycobacterium tuberculosis reveals molecular specificity of ESX protein secretion
Ekiert, D. C., & Cox, J. S. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1409345111 · Cited by 116 · see citing works
Analyses of MbtB, MbtE, and MbtF Suggest Revisions to the Mycobactin Biosynthesis Pathway in Mycobacterium tuberculosis
McMahon, M. D., Rush, J. S., & Thomas, M. G. (2012) · Journal of Bacteriology · doi:10.1128/jb.00088-12 · Cited by 115 · see citing works
SLC11A1 (formerly NRAMP1) gene polymorphisms and tuberculosis susceptibility: a meta-analysis.
Li, H. T., Zhang, T. T., Zhou, Y., Huang, Q., & Huang, J. (2006) · PubMed · Cited by 111 · see citing works
The Mycobacterium tuberculosis PE Proteins Rv0285 and Rv1386 Modulate Innate Immunity and Mediate Bacillary Survival in Macrophages
Tiwari, B., Kannan, N., Vemu, L., & Raghunand, T. R. (2012) · PLoS ONE · doi:10.1371/journal.pone.0051686 · Cited by 106 · see citing works
In vitro differentiation of human macrophages with enhanced antimycobacterial activity
Vogt, G., & Nathan, C. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57235 · Cited by 103 · see citing works
Host–Pathogen Interactions During Mycobacterium tuberculosis infections
Stanley, S. A., & Cox, J. S. (2013) · Current topics in microbiology and immunology · doi:10.1007/82_2013_332 · Cited by 101 · see citing works
Induction of CD8 T Cells against a Novel Epitope in TB10.4: Correlation with Mycobacterial Virulence and the Presence of a Functional Region of Difference-1
Billeskov, R., Lundberg, C. V., Andersen, P. L., & Dietrich, J. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.6.3973 · Cited by 100 · see citing works
Evidence inconsistent with a role for the Bcg gene (Nramp1) in resistance of mice to infection with virulent Mycobacterium tuberculosis.
Medina, E., & North, R. J. (1996) · The Journal of Experimental Medicine · doi:10.1084/jem.183.3.1045 · Cited by 97 · see citing works
The natural resistance-associated macrophage protein and susceptibility to intracellular pathogens
Bellamy, R. (1999) · Microbes and Infection · doi:10.1016/s1286-4579(99)80010-0 · Cited by 96 · see citing works
High Frequency of CD4+T Cells Specific for the TB10.4 Protein Correlates with Protection againstMycobacterium tuberculosisInfection
Hervás‐Stubbs, S., Majlessi, L., Simsova, M., Morová, J., Rojas, M.-J., Nouzé, C., Brodin, P. M., Šebo, P., & Leclerc, C. (2006) · Infection and Immunity · doi:10.1128/iai.02086-05 · Cited by 96 · see citing works
Cell Envelope Protein PPE68 Contributes to Mycobacterium tuberculosis RD1 Immunogenicity Independently of a 10-Kilodalton Culture Filtrate Protein and ESAT-6
Demangel, C., Brodin, P. M., Cockle, P. J., Brosch, R., Majlessi, L., Leclerc, C., & Cole, S. T. (2004) · Infection and Immunity · doi:10.1128/iai.72.4.2170-2176.2004 · Cited by 95 · see citing works
Mycobacterium tuberculosis Can Utilize Heme as an Iron Source
Jones, C. M., & Niederweis, M. (2011) · Journal of Bacteriology · doi:10.1128/jb.01312-10 · Cited by 94 · see citing works
Self-citation
Tubercle bacilli rely on a type VII army for pathogenicity
Stoop, E. J. M., Bitter, W., & van der Sar, A. M. (2012) · Trends in Microbiology · doi:10.1016/j.tim.2012.07.001 · Cited by 90 · see citing works
Solution Structure of the Mycobacterium tuberculosis EsxG·EsxH Complex
Ilghari, D., Lightbody, K. L., Veverka, V., Waters, L. C., Muskett, F. W., Renshaw, P. S., & Carr, M. D. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.248732 · Cited by 88 · see citing works
Mycobacterial Esx-3 Requires Multiple Components for Iron Acquisition
Siegrist, M. S., Steigedal, M., Ahmad, R., Mehra, A., Dragset, M. S., Schuster, B. M., Philips, J. A., Carr, S. A., & Rubin, E. J. (2014) · mBio · doi:10.1128/mbio.01073-14 · Cited by 87 · see citing works
Self-citation
A Replication-Limited Recombinant Mycobacterium bovis BCG Vaccine against Tuberculosis Designed for Human Immunodeficiency Virus-Positive Persons Is Safer and More Efficacious than BCG
Tullius, M. V., Harth, G., Masleša-Galić, S., Dillon, B. J., & Horwitz, M. A. (2008) · Infection and Immunity · doi:10.1128/iai.00434-08 · Cited by 82 · see citing works
ϕ 2 GFP10, a High-Intensity Fluorophage, Enables Detection and Rapid Drug Susceptibility Testing of Mycobacterium tuberculosis Directly from Sputum Samples
Jain, P., Hartman, T. E., Eisenberg, N., O’Donnell, M. R., Kriakov, J., Govender, K., Makume, M. T., Thaler, D. S., Hatfull, G. F., Sturm, A. W., et al. (2012) · Journal of Clinical Microbiology · doi:10.1128/jcm.06192-11 · Cited by 80 · see citing works
Self-citation
ESX/type VII secretion systems of mycobacteria: Insights into evolution, pathogenicity and protection
Siméone, R., Bottai, D., Frigui, W., Majlessi, L., & Brosch, R. (2015) · Tuberculosis · doi:10.1016/j.tube.2015.02.019 · Cited by 77 · see citing works
Consequence of Nramp1 Deletion to Mycobacterium tuberculosis Infection in Mice
North, R. J., LaCourse, R., Ryan, L., & Gros, P. (1999) · Infection and Immunity · doi:10.1128/iai.67.11.5811-5814.1999 · Cited by 76 · see citing works
Lipidomic discovery of deoxysiderophores reveals a revised mycobactin biosynthesis pathway in Mycobacterium tuberculosis
Madigan, C. A., Cheng, T.-Y., Layre, E., Young, D. C., McConnell, M. J., Debono, C. A., Murry, J. P., Wei, J.-R., Barry, C. E., Rodriguez, G. M., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1109958109 · Cited by 65 · see citing works
Identification of Genes Encoding Exported Mycobacterium tuberculosis Proteins Using a Tn 552′phoA In Vitro Transposition System
Braunstein, M., Griffin, T. J., Kriakov, J., Friedman, S. T., Grindley, N. D. F., & Jacobs, W. R. (2000) · Journal of Bacteriology · doi:10.1128/jb.182.10.2732-2740.2000 · Cited by 61 · see citing works
Self-citation
Lipidomic Analysis Links Mycobactin Synthase K to Iron Uptake and Virulence in M. tuberculosis
Madigan, C. A., Martinot, A. J., Wei, J.-R., Madduri, A. V. R., Cheng, T., Young, D. C., Layre, E., Murry, J. P., Rubin, E. J., & Moody, D. B. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1004792 · Cited by 52 · see citing works
Enhanced Specialized Transduction Using Recombineering in Mycobacterium tuberculosis
Tufariello, J. M., Malek, A., Vilchèze, C., Cole, L. E., Ratner, H. K., González, P. A., Jain, P., Hatfull, G. F., Larsen, M. H., & Jacobs, W. R. (2014) · mBio · doi:10.1128/mbio.01179-14 · Cited by 32 · see citing works
Self-citation
Conservation of Structure and Protein-Protein Interactions Mediated by the Secreted Mycobacterial Proteins EsxA, EsxB, and EspA
Callahan, B. P., Nguyen, K., Collins, A. M., Valdes, K. M., Caplow, M., Crossman, D. K., Steyn, A. J. C., Eisele, L. E., & Derbyshire, K. M. (2009) · Journal of Bacteriology · doi:10.1128/jb.01032-09 · Cited by 28 · see citing works
Heterologous Expression of Mycobacterial Esx Complexes in Escherichia coli for Structural Studies Is Facilitated by the Use of Maltose Binding Protein Fusions
Arbing, M. A., Chan, S., Harris, L. R., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0081753 · Cited by 25 · see citing works
Getting Across the Cell Envelope: Mycobacterial Protein Secretion
van der Woude, A. D., Luirink, J., & Bitter, W. (2012) · Current topics in microbiology and immunology · doi:10.1007/82_2012_298 · Cited by 19 · see citing works
Integration of heterogeneous molecular networks to unravel gene-regulation in Mycobacterium tuberculosis
van Dam, J. C. J., Schaap, P. J., dos Santos, V. A. P. M., & Diez, M. S. (2014) · BMC Systems Biology · doi:10.1186/s12918-014-0111-5 · Cited by 18 · see citing works
H-2 alleles contribute to antigen 85-specific interferon-gamma responses during Mycobacterium tuberculosis infection
Beamer, G., Cyktor, J. C., Carruthers, B., & Turner, J. (2011) · Cellular Immunology · doi:10.1016/j.cellimm.2011.06.002 · Cited by 8 · see citing works

Flagged first, then by citations

Sorted by citations

ESX secretion systems: mycobacterial evolution to counter host immunity
Gröschel, M. I., Sayes, F., Simeone, R., Majlessi, L., & Brosch, R. (2016) · Nature Reviews Microbiology · doi:10.1038/nrmicro.2016.131 · Cited by 382 · see citing works
Mycobacterium tuberculosis is protected from NADPH oxidase and LC3-associated phagocytosis by the LCP protein CpsA
Köster, S., Upadhyay, S., Chandra, P., Papavinasasundaram, K., Yang, G., Hassan, A., Grigsby, S. J., Mittal, E., Park, H. S., Jones, V., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1707792114 · Cited by 208 · see citing works
Self-citation
Mycobacterium tuberculosis Type VII Secretion System Effectors Differentially Impact the ESCRT Endomembrane Damage Response
Mittal, E., Skowyra, M. L., Uwase, G., Tinaztepe, E., Mehra, A., Köster, S., Hanson, P. I., & Philips, J. A. (2018) · mBio · doi:10.1128/mbio.01765-18 · Cited by 110 · see citing works
Self-citation
Systematic, multiparametric analysis of Mycobacterium tuberculosis intracellular infection offers insight into coordinated virulence
Barczak, A. K., Avraham, R., Singh, S., Luo, S. S., Zhang, W. R., Bray, M.-A., Hinman, A. E., Thompson, M., Nietupski, R. M., Golas, A., et al. (2017) · PLOS Pathogens · doi:10.1371/journal.ppat.1006363 · Cited by 120 · see citing works
Functional characterization of the Mycobacterium abscessus genome coupled with condition specific transcriptomics reveals conserved molecular strategies for host adaptation and persistence
Miranda-CasoLuengo, A. A., Staunton, P. M., Dinan, A. M., Lohan, A. J., & Loftus, B. J. (2016) · BMC Genomics · doi:10.1186/s12864-016-2868-y · Cited by 81 · see citing works
Blending genomes: distributive conjugal transfer in mycobacteria, a sexier form of HGT
Gray, T. A., & Derbyshire, K. M. (2018) · Molecular Microbiology · doi:10.1111/mmi.13971 · Cited by 70 · see citing works
Toxin secretion and trafficking by Mycobacterium tuberculosis
Pajuelo, D., Tak, U., Zhang, L., Danilchanka, O., Tischler, A. D., & Niederweis, M. (2021) · Nature Communications · doi:10.1038/s41467-021-26925-1 · Cited by 63 · see citing works
Self-citation
ESX/Type VII Secretion Systems—An Important Way Out for Mycobacterial Proteins
Vaziri, F., & Brosch, R. (2019) · Microbiology Spectrum · doi:10.1128/microbiolspec.psib-0029-2019 · Cited by 50 · see citing works
Structure and Function of the Mycobacterial Type VII Secretion Systems
Bunduc, C. M., Bitter, W., & Houben, E. N. G. (2020) · Annual Review of Microbiology · doi:10.1146/annurev-micro-012420-081657 · Cited by 50 · see citing works
Genome-wide Phenotypic Profiling Identifies and Categorizes Genes Required for Mycobacterial Low Iron Fitness
Dragset, M. S., Ioerger, T. R., Zhang, Y. J., Mærk, M., Ginbot, Z., Sacchettini, J. C., Flo, T. H., Rubin, E. J., & Steigedal, M. (2019) · Scientific Reports · doi:10.1038/s41598-019-47905-y · Cited by 49 · see citing works
Esx Systems and the Mycobacterial Cell Envelope: What's the Connection?
Bosserman, R. E., & Champion, P. A. (2017) · Journal of Bacteriology · doi:10.1128/jb.00131-17 · Cited by 42 · see citing works
Bacterial secretion chaperones: the mycobacterial type VII case
Phan, T. H., & Houben, E. N. G. (2018) · FEMS Microbiology Letters · doi:10.1093/femsle/fny197 · Cited by 37 · see citing works
Conserved and specialized functions of Type VII secretion systems in non-tuberculous mycobacteria: This article was corrected to a Review article on 05 August 2021
Lagune, M., Petit, C., Sotomayor, F. V., Johansen, M. D., Beckham, K. S. H., Ritter, C., Girard-Misguich, F., Wilmanns, M., Kremer, L., Maurer, F. P., et al. (2021) · Microbiology · doi:10.1099/mic.0.001054 · Cited by 27 · see citing works
Mycosins of the Mycobacterial Type VII ESX Secretion System: the Glue That Holds the Party Together
Chen, J. M. (2016) · mBio · doi:10.1128/mbio.02062-16 · Cited by 10 · see citing works

Research progress on virulence-related genes of Mycobacterium tuberculosis
Ding, Z., & Du, X. (2010) · Chinese Journal of Asthma · doi:10.3760/cma.j.issn.1673-436x.2010.012.005
Intracellular survival of virulence and low-virulence strains of Vibrio parahaemolyticus in Epinephelus awoara macrophages and peripheral leukocytes
Xu, X., Sang, B., Chen, W. B., Yan, Q., Xiong, Z. Y., Su, J., & Zou, W. (2015) · Genetics and Molecular Research · doi:10.4238/2015.january.30.14 · Cited by 10 · see citing works
Transcriptional signatures of Mycobacterium tuberculosis in mouse model of intraocular tuberculosis
Abhishek, S., Ryndak, M. B., Choudhary, A., Sharma, S., Gupta, A., Gupta, V., Singh, N., Laal, S., & Verma, I. (2019) · Pathogens and Disease · doi:10.1093/femspd/ftz045 · Cited by 9 · see citing works
Transcriptional Biomarkers of Differentially Detectable Mycobacterium tuberculosis in Patient Sputum
Zainabadi, K., Saito, K., Mishra, S., et al. (2022) · mBio · doi:10.1128/mbio.02701-22 · Cited by 9 · see citing works
[Virulence of Mycobacterium tuberculosis. II. Comparison of virulence of Mycobacterium tuberculosis constantly exposed to oxygen or nitrogen flow based upon a recently introduced virulence test pathogenicity standard].
Kostrzeński, W., & Paklerska-Pobratyn, H. (1959) · PubMed

Authors: Tufariello, J. M., Chapman, J. R., Kerantzas, C. A., Wong, K.-W., Vilchèze, C., Jones, C. M., Cole, L. E., Tinaztepe, E., Thompson, V., Fenyö, D., Niederweis, M., Ueberheide, B., Philips, J. A., & Jacobs, W. R.
Affiliations: Albert Einstein College of Medicine (US)
New York University (US)
Shanghai Medical College of Fudan University (CN)
University of Alabama at Birmingham (US)
NYU Langone Health (US)
ORCID: Tufariello, JoAnn M.
Chapman, Jessica R.
Kerantzas, Christopher A.
Wong, Ka-Wing
Vilchèze, Catherine
Jones, Christopher M.
Fenyö, David
Niederweis, Michael
Ueberheide, Beatrix
Philips, Jennifer A.
Jacobs, William R.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2016-01-04
Volume: 113
Issue: 3
Pages: E348-57
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1523321113
PMC: PMC4725510
OpenAlex: W2225338927
Cited by: 215
References: 78
Citations by year: 2026: 20 · 2025: 26 · 2024: 15 · 2023: 20 · 2022: 23 · 2021: 20 · 2020: 18 · 2019: 25 · 2018: 19 · 2017: 17 · 2016: 12
FWCI: 22.45
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.pnas.org/preview_site/misc/userlicense.xhtml (vor, 182 d)
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: HHS | NIH | National Institute of Allergy and Infectious Diseases (AI26170, AI098925, AI087682)
Doris Duke Charitable Foundation (0000000)
New York University School of Medicine (0000000)
Topics: Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
Keywords: Mycobacterium tuberculosis, type VII secretion system, iron acquisition, siderophores, mycobactin, virulence, host-pathogen interaction, metal homeostasis, culture filtrate proteins
MeSH terms: Aerosols, Animals, Bacterial Proteins, Genotype, Hemin, Humans, Iron, Macrophages, Mice, Inbred C57BL, Mutation, Mycobacterium tuberculosis, Oxazoles, Phenotype, Mass Spectrometry, Substrate Specificity, Virulence, Mice, SCID, Cell Polarity, Siderophores, Mice, Knockout, Homeodomain Proteins, Proteomics, 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.

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

Separable roles for Mycobacterium tuberculosis ESX-3 effectors in iron acquisition and virulence

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Self-check

Cites

Cited by

Related

Record

About these checks