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Article ; Online: Disconnecting in vitro ESX-1 secretion from mycobacterial virulence.

2013 Volume 195, Issue 24, Page(s) 5418–5420

MeSH term(s)	Animals ; Antigens, Bacterial ; Bacterial Proteins/metabolism ; Humans ; Membrane Transport Proteins/genetics ; Membrane Transport Proteins/metabolism ; Mycobacterium tuberculosis/pathogenicity
Chemical Substances	Antigens, Bacterial ; Bacterial Proteins ; CFP-10 protein, Mycobacterium tuberculosis ; ESAT-6 protein, Mycobacterium tuberculosis ; Membrane Transport Proteins
Language	English
Publishing date	2013-10-11
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2968-3
ISSN	1098-5530 ; 0021-9193
ISSN (online)	1098-5530
ISSN	0021-9193
DOI	10.1128/JB.01145-13
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Article ; Online: Correlation of phenotypic profiles using targeted proteomics identifies mycobacterial esx-1 substrates.

Champion, Matthew M / Williams, Emily A / Pinapati, Richard S / Champion, Patricia A DiGiuseppe

Journal of proteome research

2014 Volume 13, Issue 11, Page(s) 5151–5164

Abstract: The Esx/WXG-100 (ESAT-6/Wss) exporters are multiprotein complexes that promote protein translocation across the cytoplasmic membrane in a diverse range of pathogenic and nonpathogenic bacterial species. The Esx-1 (ESAT-6 System-1) system mediates ... ...

Abstract	The Esx/WXG-100 (ESAT-6/Wss) exporters are multiprotein complexes that promote protein translocation across the cytoplasmic membrane in a diverse range of pathogenic and nonpathogenic bacterial species. The Esx-1 (ESAT-6 System-1) system mediates virulence factor translocation in mycobacterial pathogens, including the human pathogen Mycobacterium tuberculosis. Although several genes have been associated with Esx-1-mediated transport and virulence, the contribution of individual Esx-1 genes to export is largely undefined. A unique aspect of Esx-1 export is that several substrates require each other for export/stability. We exploited substrate "codependency" to identify Esx-1 substrates. We simultaneously quantified changes in the levels of 13 Esx-1 proteins from both secreted and cytosolic protein fractions generated from 16 Esx-1-deficient Mycobacterium marinum strains in a single experiment using MRM/SRM targeted mass spectrometry. This expansion of measurable Esx-1 proteins allowed us to define statistical rules for assigning novel substrates using phenotypic profiles of known Esx-1 substrates. Using this approach, we identified three additional Esx-1 substrates encoded by the esx-1 region. Our studies begin to address how disruption of specific genes affects several proteins in the Esx-1 complex. Overall, our findings illuminate relationships between Esx-1 proteins and create a framework for the identification of secreted substrates applicable to other protein exporters and pathways.
MeSH term(s)	Antigens, Bacterial/genetics ; Antigens, Bacterial/metabolism ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Mass Spectrometry/methods ; Mycobacterium marinum/genetics ; Mycobacterium marinum/metabolism ; Mycobacterium marinum/pathogenicity ; Phenotype ; Protein Interaction Mapping ; Protein Transport ; Proteomics/methods ; Reproducibility of Results
Chemical Substances	Antigens, Bacterial ; Bacterial Proteins ; ESAT-6 protein, Mycobacterium tuberculosis
Language	English
Publishing date	2014-08-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/pr500484w
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Article ; Online: A novel ESX-1 locus reveals that surface-associated ESX-1 substrates mediate virulence in Mycobacterium marinum.

Kennedy, George M / Hooley, Gwendolyn C / Champion, Matthew M / Mba Medie, Felix / Champion, Patricia A DiGiuseppe

Journal of bacteriology

2014 Volume 196, Issue 10, Page(s) 1877–1888

Abstract: EsxA (ESAT-6) and EsxB (CFP-10) are virulence factors exported by the ESX-1 system in mycobacterial pathogens. In Mycobacterium marinum, an established model for ESX-1 secretion in Mycobacterium tuberculosis, genes required for ESX-1 export reside at the ...

Abstract	EsxA (ESAT-6) and EsxB (CFP-10) are virulence factors exported by the ESX-1 system in mycobacterial pathogens. In Mycobacterium marinum, an established model for ESX-1 secretion in Mycobacterium tuberculosis, genes required for ESX-1 export reside at the extended region of difference 1 (RD1) locus. In this study, a novel locus required for ESX-1 export in M. marinum was identified outside the RD1 locus. An M. marinum strain bearing a transposon-insertion between the MMAR_1663 and MMAR_1664 genes exhibited smooth-colony morphology, was deficient for ESX-1 export, was nonhemolytic, and was attenuated for virulence. Genetic complementation revealed a restoration of colony morphology and a partial restoration of virulence in cell culture models. Yet hemolysis and the export of ESX-1 substrates into the bacteriological medium in vitro as measured by both immunoblotting and quantitative proteomics were not restored. We show that genetic complementation of the transposon insertion strain partially restored the translocation of EsxA and EsxB to the mycobacterial cell surface. Our findings indicate that the export of EsxA and EsxB to the cell surface, rather than secretion into the bacteriological medium, correlates with virulence in M. marinum. Together, these findings not only expand the known genetic loci required for ESX-1 secretion in M. marinum but also provide an explanation for the observed disparity between in vitro ESX-1 export and virulence.
MeSH term(s)	Acanthamoeba castellanii ; Animals ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Cell Line ; Cell Membrane/metabolism ; Cell Survival ; Gene Expression Regulation, Bacterial/physiology ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Macrophages ; Mice ; Mycobacterium marinum/genetics ; Mycobacterium marinum/metabolism ; Mycobacterium marinum/pathogenicity ; Mycobacterium tuberculosis/metabolism ; Protein Transport ; Virulence ; Virulence Factors
Chemical Substances	Bacterial Proteins ; Homeodomain Proteins ; Virulence Factors
Language	English
Publishing date	2014-03-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2968-3
ISSN	1098-5530 ; 0021-9193
ISSN (online)	1098-5530
ISSN	0021-9193
DOI	10.1128/JB.01502-14
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Article ; Online: Homeostasis of N-α-terminal acetylation of EsxA correlates with virulence in Mycobacterium marinum.

Mba Medie, Felix / Champion, Matthew M / Williams, Emily A / Champion, Patricia A DiGiuseppe

Infection and immunity

2014 Volume 82, Issue 11, Page(s) 4572–4586

Abstract: The mycobacterial Esx-1 (ESAT-6 system 1) exporter translocates virulence factors across the cytoplasmic membrane to the cell wall, cell surface, and the bacteriological medium in vitro. The mechanisms underlying substrate targeting to distinct locations ...

Abstract	The mycobacterial Esx-1 (ESAT-6 system 1) exporter translocates virulence factors across the cytoplasmic membrane to the cell wall, cell surface, and the bacteriological medium in vitro. The mechanisms underlying substrate targeting to distinct locations are unknown. Several Esx-1 substrates are N-α-terminally acetylated. The role of this rare modification in bacteria is unclear. We sought to identify genes required for Esx-1 substrate modification, transport, and localization. Pathogenic mycobacteria lyse Acanthamoeba castellanii in an Esx-1-dependent manner. We conducted a genetic screen to identify Mycobacterium marinum strains which failed to lyse amoebae. We identified a noncytotoxic M. marinum strain with a transposon insertion in a predicted N-α-terminal acetyltransferase not previously linked to mycobacterial pathogenesis. Disruption of this gene led to attenuation of virulence, failure to induce a type I interferon response during macrophage infection, and loss of hemolytic activity. The major Esx-1 substrates, EsxA and EsxB, were exported to the cell surface, but only low levels were released into the bacteriological medium. The balance of EsxA N-α-terminal acetylation was disrupted, resulting in a mycobacterial strain in which surface-associated EsxA was hyperacetylated. Genetic complementation completely restored Esx-1 function and the levels of N-α-terminally acetylated EsxA on the surface but restored only low levels of Esx-1 substrates in the bacteriological medium. Our results reveal a novel gene required for mycobacterial Esx-1 export. Our findings indicate that maintaining the homeostasis of Esx-1 substrate N-α-terminal acetylation is essential for Esx-1-mediated virulence. We propose an inverse correlation between EsxA acetylation and virulence.
MeSH term(s)	Acanthamoeba castellanii/microbiology ; Acetylation ; Animals ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Cell Line ; Gene Expression Regulation, Bacterial/physiology ; Homeostasis/physiology ; Macrophages ; Mice ; Models, Molecular ; Mycobacterium marinum/genetics ; Mycobacterium marinum/metabolism ; Mycobacterium marinum/pathogenicity ; Protein Conformation ; Virulence
Chemical Substances	Bacterial Proteins
Language	English
Publishing date	2014-08-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218698-6
ISSN	1098-5522 ; 0019-9567
ISSN (online)	1098-5522
ISSN	0019-9567
DOI	10.1128/IAI.02153-14
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Article ; Online: Conserved mechanisms of Mycobacterium marinum pathogenesis within the environmental amoeba Acanthamoeba castellanii.

Kennedy, George M / Morisaki, J Hiroshi / Champion, Patricia A DiGiuseppe

Applied and environmental microbiology

2012 Volume 78, Issue 6, Page(s) 2049–2052

Abstract: Mycobacterium marinum is a waterborne mycobacterial pathogen. Due to their common niche, protozoa likely represent natural hosts for M. marinum. We demonstrate that the ESX-1 secretion system is required for M. marinum pathogenesis and that M. marinum ... ...

Abstract	Mycobacterium marinum is a waterborne mycobacterial pathogen. Due to their common niche, protozoa likely represent natural hosts for M. marinum. We demonstrate that the ESX-1 secretion system is required for M. marinum pathogenesis and that M. marinum utilizes actin-based motility in amoebae. Therefore, at least two virulence pathways used by M. marinum in macrophages are conserved during M. marinum infection of amoebae.
MeSH term(s)	Acanthamoeba castellanii/microbiology ; Actins/metabolism ; Environmental Microbiology ; Macrophages/microbiology ; Mycobacterium marinum/pathogenicity ; Protozoan Proteins/metabolism
Chemical Substances	Actins ; Protozoan Proteins
Language	English
Publishing date	2012-01-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	223011-2
ISSN	1098-5336 ; 0099-2240
ISSN (online)	1098-5336
ISSN	0099-2240
DOI	10.1128/AEM.06965-11
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Article: Correlation of Phenotypic Profiles Using Targeted Proteomics Identifies Mycobacterial Esx-1 Substrates

Champion, Matthew M / Williams, Emily A / Pinapati, RichardS / Champion, Patricia A. DiGiuseppe

Journal of Proteome Research. 2014 Nov. 07, v. 13, no. 11

2014

Abstract	The Esx/WXG-100 (ESAT-6/Wss) exporters are multiprotein complexes that promote protein translocation across the cytoplasmic membrane in a diverse range of pathogenic and nonpathogenic bacterial species. The Esx-1 (ESAT-6 System-1) system mediates virulence factor translocation in mycobacterial pathogens, including the human pathogen Mycobacterium tuberculosis. Although several genes have been associated with Esx-1-mediated transport and virulence, the contribution of individual Esx-1 genes to export is largely undefined. A unique aspect of Esx-1 export is that several substrates require each other for export/stability. We exploited substrate “codependency” to identify Esx-1 substrates. We simultaneously quantified changes in the levels of 13 Esx-1 proteins from both secreted and cytosolic protein fractions generated from 16 Esx-1-deficient Mycobacterium marinum strains in a single experiment using MRM/SRM targeted mass spectrometry. This expansion of measurable Esx-1 proteins allowed us to define statistical rules for assigning novel substrates using phenotypic profiles of known Esx-1 substrates. Using this approach, we identified three additional Esx-1 substrates encoded by the esx-1 region. Our studies begin to address how disruption of specific genes affects several proteins in the Esx-1 complex. Overall, our findings illuminate relationships between Esx-1 proteins and create a framework for the identification of secreted substrates applicable to other protein exporters and pathways.
Keywords	Mycobacterium marinum ; Mycobacterium tuberculosis ; animal pathogens ; cell membranes ; genes ; mass spectrometry ; multiprotein complexes ; phenotype ; protein transport ; proteome ; proteomics ; virulence
Language	English
Dates of publication	2014-1107
Size	p. 5151-5164.
Publishing place	American Chemical Society
Document type	Article
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021%2Fpr500484w
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Direct detection of bacterial protein secretion using whole colony proteomics.

Champion, Matthew M / Williams, Emily A / Kennedy, George M / Champion, Patricia A DiGiuseppe

Molecular & cellular proteomics : MCP

2012 Volume 11, Issue 9, Page(s) 596–604

Abstract: Bacteria use a variety of secretion systems to transport proteins beyond their cell membrane to interact with their environment. For bacterial pathogens, these systems are key virulence determinants that transport bacterial proteins into host cells. ... ...

Abstract	Bacteria use a variety of secretion systems to transport proteins beyond their cell membrane to interact with their environment. For bacterial pathogens, these systems are key virulence determinants that transport bacterial proteins into host cells. Genetic screens to identify bacterial genes required for export have relied on enzymatic or fluorescent reporters fused to known substrates to monitor secretion. However, they cannot be used in analysis of all secretion systems, limiting the implementation across bacteria. Here, we introduce the first application of a modified form of whole colony MALDI-TOF MS to directly detect protein secretion from intact bacterial colonies. We show that this method is able to specifically monitor the ESX-1 system protein secretion system, a major virulence determinant in both mycobacterial and Gram-positive pathogens that is refractory to reporter analysis. We validate the use of this technology as a high throughput screening tool by identifying an ESAT-6 system 1-deficient mutant from a Mycobacterium marinum transposon insertion library. Furthermore, we also demonstrate detection of secreted proteins of the prevalent type III secretion system from the Gram-negative pathogen, Pseudomonas aeruginosa. This method will be broadly applicable to study other bacterial protein export systems and for the identification of compounds that inhibit bacterial protein secretion.
MeSH term(s)	Antigens, Bacterial/genetics ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Bacterial Secretion Systems ; Mycobacterium marinum/cytology ; Mycobacterium marinum/genetics ; Mycobacterium marinum/metabolism ; Proteomics ; Pseudomonas aeruginosa/cytology ; Pseudomonas aeruginosa/metabolism ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Chemical Substances	Antigens, Bacterial ; Bacterial Proteins ; Bacterial Secretion Systems ; ESAT-6 protein, Mycobacterium tuberculosis
Language	English
Publishing date	2012-05-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2075924-1
ISSN	1535-9484 ; 1535-9476
ISSN (online)	1535-9484
ISSN	1535-9476
DOI	10.1074/mcp.M112.017533
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Article ; Online: To catch a killer. What can mycobacterial models teach us about Mycobacterium tuberculosis pathogenesis?

Shiloh, Michael U / Champion, Patricia A DiGiuseppe

Current opinion in microbiology

2009 Volume 13, Issue 1, Page(s) 86–92

Abstract: Mycobacterium tuberculosis is the causative agent of the global tuberculosis epidemic. To combat this successful human pathogen we need a better understanding of the basic biology of mycobacterial pathogenesis. The use of mycobacterial model systems has ... ...

Abstract	Mycobacterium tuberculosis is the causative agent of the global tuberculosis epidemic. To combat this successful human pathogen we need a better understanding of the basic biology of mycobacterial pathogenesis. The use of mycobacterial model systems has the potential to greatly facilitate our understanding of how M. tuberculosis causes disease. Recently, studies using mycobacterial models, including M. bovis BCG, M. marinum, and M. smegmatis have significantly contributed to understanding M. tuberculosis. Specifically, there have been advances in genetic manipulation of M. tuberculosis using inducible promoters and recombineering that alleviate technical limitations in working with mycobacteria. Model systems have helped elucidate how secretion systems function at both the molecular level and during virulence. Mycobacterial models have also led to interesting hypotheses about how M. tuberculosis mediates latent infection and host response. While there is utility in using model systems to understand tuberculosis, each of these models represent distinct mycobacterial species with unique environmental adaptations. Directly comparing findings in model mycobacteria to those in M. tuberculosis will illuminate the similarities and differences between these species and increase our understanding of why M. tuberculosis is such a potent human pathogen.
MeSH term(s)	Host-Pathogen Interactions ; Humans ; Models, Biological ; Mycobacterium bovis/genetics ; Mycobacterium bovis/pathogenicity ; Mycobacterium smegmatis/genetics ; Mycobacterium smegmatis/pathogenicity ; Mycobacterium tuberculosis/genetics ; Mycobacterium tuberculosis/pathogenicity ; Tuberculosis/immunology ; Tuberculosis/microbiology ; Tuberculosis/pathology ; Virulence
Language	English
Publishing date	2009-12-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1418474-6
ISSN	1879-0364 ; 1369-5274
ISSN (online)	1879-0364
ISSN	1369-5274
DOI	10.1016/j.mib.2009.11.006
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Article: Protein secretion systems in Mycobacteria.

Champion, Patricia A DiGiuseppe / Cox, Jeffery S

Cellular microbiology

2007 Volume 9, Issue 6, Page(s) 1376–1384

Abstract: Mycobacteria have a unique cell-envelope structure which protects the bacteria from the extracellular environment by limiting access to noxious molecules from the outside. This extremely hydrophobic and thick barrier also poses a unique problem for the ... ...

Abstract	Mycobacteria have a unique cell-envelope structure which protects the bacteria from the extracellular environment by limiting access to noxious molecules from the outside. This extremely hydrophobic and thick barrier also poses a unique problem for the export of bacterial products. Here we review the multiple protein secretion pathways in Mycobacteria, including the general secretion pathway and the Twin-Arginine Transporter, with an emphasis on the ESX-1 alternate secretion system. This newly identified protein secretion system is required for growth during infection and has provided insight into how M. tuberculosis manipulates the host immune response during infection.
MeSH term(s)	Bacterial Proteins/metabolism ; Membrane Transport Proteins/metabolism ; Mycobacterium/metabolism ; Protein Transport
Chemical Substances	Bacterial Proteins ; Membrane Transport Proteins
Language	English
Publishing date	2007-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1468320-9
ISSN	1462-5822 ; 1462-5814
ISSN (online)	1462-5822
ISSN	1462-5814
DOI	10.1111/j.1462-5822.2007.00943.x
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Article ; Online: The Carbonic Anhydrase Inhibitor Ethoxzolamide Inhibits the Mycobacterium tuberculosis PhoPR Regulon and Esx-1 Secretion and Attenuates Virulence.

Johnson, Benjamin K / Colvin, Christopher J / Needle, David B / Mba Medie, Felix / Champion, Patricia A DiGiuseppe / Abramovitch, Robert B

Antimicrobial agents and chemotherapy

2015 Volume 59, Issue 8, Page(s) 4436–4445

Abstract: Mycobacterium tuberculosis must sense and adapt to host environmental cues to establish and maintain an infection. The two-component regulatory system PhoPR plays a central role in sensing and responding to acidic pH within the macrophage and is required ...

Abstract	Mycobacterium tuberculosis must sense and adapt to host environmental cues to establish and maintain an infection. The two-component regulatory system PhoPR plays a central role in sensing and responding to acidic pH within the macrophage and is required for M. tuberculosis intracellular replication and growth in vivo. Therefore, the isolation of compounds that inhibit PhoPR-dependent adaptation may identify new antivirulence therapies to treat tuberculosis. Here, we report that the carbonic anhydrase inhibitor ethoxzolamide inhibits the PhoPR regulon and reduces pathogen virulence. We show that treatment of M. tuberculosis with ethoxzolamide recapitulates phoPR mutant phenotypes, including downregulation of the core PhoPR regulon, altered accumulation of virulence-associated lipids, and inhibition of Esx-1 protein secretion. Quantitative single-cell imaging of a PhoPR-dependent fluorescent reporter strain demonstrates that ethoxzolamide inhibits PhoPR-regulated genes in infected macrophages and mouse lungs. Moreover, ethoxzolamide reduces M. tuberculosis growth in both macrophages and infected mice. Ethoxzolamide inhibits M. tuberculosis carbonic anhydrase activity, supporting a previously unrecognized link between carbonic anhydrase activity and PhoPR signaling. We propose that ethoxzolamide may be pursued as a new class of antivirulence therapy that functions by modulating expression of the PhoPR regulon and Esx-1-dependent virulence.
MeSH term(s)	Animals ; Antigens, Bacterial/genetics ; Antigens, Bacterial/metabolism ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Carbonic Anhydrase Inhibitors/pharmacology ; Carbonic Anhydrases/genetics ; Carbonic Anhydrases/metabolism ; Cells, Cultured ; Down-Regulation/drug effects ; Down-Regulation/genetics ; Ethoxzolamide/pharmacology ; Gene Expression Regulation, Bacterial/drug effects ; Gene Expression Regulation, Bacterial/genetics ; Macrophages/drug effects ; Macrophages/metabolism ; Macrophages/microbiology ; Mice ; Mice, Inbred C57BL ; Mutation/drug effects ; Mutation/genetics ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/genetics ; Mycobacterium tuberculosis/metabolism ; Regulon/drug effects ; Tuberculosis/drug therapy ; Tuberculosis/genetics ; Tuberculosis/metabolism ; Tuberculosis/microbiology ; Virulence/drug effects ; Virulence/genetics
Chemical Substances	Antigens, Bacterial ; Bacterial Proteins ; Carbonic Anhydrase Inhibitors ; ESAT-6 protein, Mycobacterium tuberculosis ; Carbonic Anhydrases (EC 4.2.1.1) ; Ethoxzolamide (Z52H4811WX)
Language	English
Publishing date	2015-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.00719-15
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