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Bacterial Type IV Secretion: Cellular, Molecular, and Evolutionary Basis of the Subversion of Host Cell Functions by Translocated Effector Proteins

English title Bacterial Type IV Secretion: Cellular, Molecular, and Evolutionary Basis of the Subversion of Host Cell Functions by Translocated Effector Proteins
Applicant Dehio Christoph
Number 132979
Funding scheme Project funding (Div. I-III)
Research institution Abteilung Mikrobiologie Biozentrum Universität Basel
Institution of higher education University of Basel - BS
Main discipline Molecular Biology
Start/End 01.10.2010 - 30.09.2013
Approved amount 755'000.00
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All Disciplines (3)

Discipline
Molecular Biology
Medical Microbiology
Cellular Biology, Cytology

Keywords (12)

bacterial pathogenesis; chronic infection; type IV secretion systems; translocted bacterial effector protein; apoptosis; cytoskeleton; host adaptation; Bartonella; Brucella; Bacterial Type IV Secretion; Cellular;

Lay Summary (English)

Lead
Lay summary
The type IV secretion (T4S) systems of gram-negative bacteria are versatile nano-machines involved in processes relevant to bacterial infection, such as horizontal transfer of virulence and antibiotic resistance genes between bacteria, and the translocation of bacterial effector proteins into eukaryotic target cells. Effector-translocating T4S systems are widely distributed among human pathogenic bacteria that are mostly causing chronic infections, including Helicobacter pylori (causing gastritis and gastric cancer), Legionella pneumophila (causing Legionnaires disease), Bartonella spp. (causing bartonellosis) and Brucella spp. (causing brucellosis). In recent years we have - with support from the SNF (grants 3100-061777 and 31003A-109925) - established Bartonella as a powerful model for studying the cellular, molecular and evolutionary basis of T4S in bacterial pathogenesis. In the frame of the proposed project we will continue to explore this paradigmatic model of T4S. Moreover, we will expand the successful approach for studying T4S as established for Bartonella to the closely related pathogen Brucella - the etiological agent of the most important bacterial zoonosis worldwide that causes chronic infections in various mammals. We will apply a multidisciplinary experimental approach including bacterial genetics, cell biology, molecular biology, biochemistry, structural biology, genomics, and animal experimentation. In subproject A targeting T4S in Bartonella, we will perform a structure/function analysis of the T4S system-translocated effector proteins and their cellular targets, and study molecular evolutionary mechanisms of host adaptation mediated by these effectors. In subproject B targeting T4S in Brucella, we will focus on the characterization of the T4S-dependent intracellular trafficking route of Brucella resulting in the establishment of an endoplasmic reticulum-associated replication niche, the systematic identification of the involved host factors and the structure/function analysis of the T4S effectors interacting with the identified host factors. By studying the molecular mechanism of T4S in the closely related pathogens Bartonella and Brucella, we anticipate to provide fundamental contributions to our understanding how this wide-spread virulence mechanism facilitates chronic bacterial infection, which may also help to design novel strategies to combat bacterial virulence. Based on the specific subversion of multiple cellular functions by the T4S effectors of these pathogens we also expect to contribute new basic knowledge and novel tools to different fields of cell biology.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
A translocation motif in relaxase TrwC specifically affects recruitment by its conjugative type IV secretion system.
Alperi Anabel, Larrea Delfina, Fernández-González Esther, Dehio Christoph, Zechner Ellen L, Llosa Matxalen (2013), A translocation motif in relaxase TrwC specifically affects recruitment by its conjugative type IV secretion system., in Journal of Bacteriology, 195(22), 4999-5006.
Bartonella and Brucella--weapons and strategies for stealth attack.
Ben-Tekaya Houchaima, Gorvel Jean-Pierre, Dehio Christoph (2013), Bartonella and Brucella--weapons and strategies for stealth attack., in Cold Spring Harbor perspectives in medicine, 3(8), 1-8.
Bartonella henselae trimeric autotransporter adhesin BadA expression interferes with effector translocation by the VirB/D4 type IV secretion system.
Lu Yun-Yueh, Franz Bettina, Truttmann Matthias C, Riess Tanja, Gay-Fraret Jérémie, Faustmann Marco, Kempf Volkhard A J, Dehio Christoph (2013), Bartonella henselae trimeric autotransporter adhesin BadA expression interferes with effector translocation by the VirB/D4 type IV secretion system., in Cellular microbiology, 15(5), 759-78.
Conserved inhibitory mechanism and competent ATP binding mode for adenylyltransferases with Fic fold.
Goepfert Arnaud, Stanger Frédéric V, Dehio Christoph, Schirmer Tilman (2013), Conserved inhibitory mechanism and competent ATP binding mode for adenylyltransferases with Fic fold., in PloS One, 8(5), 64901-64901.
Directed shotgun proteomics guided by saturated RNA-seq identifies a complete expressed prokaryotic proteome.
Omasits Ulrich, Quebatte Maxime, Stekhoven Daniel J, Fortes Claudia, Roschitzki Bernd, Robinson Mark D, Dehio Christoph, Ahrens Christian H (2013), Directed shotgun proteomics guided by saturated RNA-seq identifies a complete expressed prokaryotic proteome., in Genome research, 23(11), 1916-27.
Dual input control: activation of the Bartonella henselae VirB/D4 type IV secretion system by the stringent sigma factor RpoH1 and the BatR/BatS two-component system.
Québatte Maxime, Dick Mathias S, Kaever Volkhard, Schmidt Alexander, Dehio Christoph (2013), Dual input control: activation of the Bartonella henselae VirB/D4 type IV secretion system by the stringent sigma factor RpoH1 and the BatR/BatS two-component system., in Molecular microbiology, 90(4), 756-75.
Multi-scale Gaussian representation and outline-learning based cell image segmentation.
Farhan Muhammad, Ruusuvuori Pekka, Emmenlauer Mario, Rämö Pauli, Dehio Christoph, Yli-Harja Olli (2013), Multi-scale Gaussian representation and outline-learning based cell image segmentation., in BMC bioinformatics, 14 (Suppl 10), 6-6.
Partial disruption of translational and posttranslational machinery reshapes growth rates of Bartonella birtlesii.
Rolain Jean Marc, Vayssier-Taussat Muriel, Saisongkorh Watcharee, Merhej Vicky, Gimenez Gregory, Robert Catherine, Le Rhun Danielle, Dehio Christoph, Raoult Didier (2013), Partial disruption of translational and posttranslational machinery reshapes growth rates of Bartonella birtlesii., in mBio, 4(2), 00115-13.
Systems-level analysis of host-pathogen interaction using RNA interference.
Eicher Simone C, Dehio Christoph (2013), Systems-level analysis of host-pathogen interaction using RNA interference., in New biotechnology, 30(3), 308-13.
Adenylylation control by intra- or intermolecular active site obstruction in Fic proteins
Engel P., Goepfert A., Stanger F.V., Harms A., Schmidt A., Schirmer T., Dehio C. (2012), Adenylylation control by intra- or intermolecular active site obstruction in Fic proteins, in Nature, 482(7383), 107-110.
Adenylylation control by intra- or intermolecular active-site obstruction in Fic proteins.
Engel Philipp, Goepfert Arnaud, Stanger Frédéric V, Harms Alexander, Schmidt Alexander, Schirmer Tilman, Dehio Christoph (2012), Adenylylation control by intra- or intermolecular active-site obstruction in Fic proteins., in Nature, 482(7383), 107-10.
Bacterial effector binds host cell adenylyl cyclase to potentiate Gαs-dependent cAMP production.
Pulliainen Arto T, Pieles Kathrin, Brand Cameron S, Hauert Barbara, Böhm Alex, Quebatte Maxime, Wepf Alexander, Gstaiger Matthias, Aebersold Ruedi, Dessauer Carmen W, Dehio Christoph (2012), Bacterial effector binds host cell adenylyl cyclase to potentiate Gαs-dependent cAMP production., in Proceedings of the National Academy of Sciences of the United States of America, 109(24), 9581-6.
Bacterial effector binds host cell adenylyl cyclase to potentiate Gαs-dependent cAMP production.
Pulliainen Arto T, Pieles Kathrin, Brand Cameron S, Hauert Barbara, Böhm Alex, Quebatte Maxime, Wepf Alexander, Gstaiger Matthias, Aebersold Ruedi, Dessauer Carmen W, Dehio Christoph (2012), Bacterial effector binds host cell adenylyl cyclase to potentiate Gαs-dependent cAMP production., in Proceedings of the National Academy of Sciences of the United States of America, 109(24), 9581-6.
Bartonella entry mechanisms into mammalian host cells.
Eicher Simone C, Dehio Christoph (2012), Bartonella entry mechanisms into mammalian host cells., in Cellular microbiology, 14(8), 1166-73.
Bartonella entry mechanisms into mammalian host cells.
Eicher Simone C, Dehio Christoph (2012), Bartonella entry mechanisms into mammalian host cells., in Cellular microbiology, 14(8), 1166-73.
Bartonella henselae trimeric autotransporter adhesin BadA expression interferes with effector translocation by the VirB/D4 type IV secretion system.
Lu Yun-Yueh, Franz Bettina, Truttmann Matthias C, Riess Tanja, Gay-Fraret Jérémie, Faustmann Marco, Kempf Volkhard A J, Dehio Christoph (2012), Bartonella henselae trimeric autotransporter adhesin BadA expression interferes with effector translocation by the VirB/D4 type IV secretion system., in Cellular microbiology, in press, in press.
Intruders below the radar: Molecular Pathogenesis of Bartonella spp.
Harms A., Dehio C. (2012), Intruders below the radar: Molecular Pathogenesis of Bartonella spp., in Clinical Microbiology Reviews, 25(1), 42-78.
Intruders below the radar: molecular pathogenesis of Bartonella spp.
Harms Alexander, Dehio Christoph (2012), Intruders below the radar: molecular pathogenesis of Bartonella spp., in Clinical microbiology reviews, 25(1), 42-78.
New perspectives into bacterial DNA transfer to human cells.
Llosa Matxalen, Schröder Gunnar, Dehio Christoph (2012), New perspectives into bacterial DNA transfer to human cells., in Trends in microbiology, 20(8), 355-9.
New perspectives into bacterial DNA transfer to human cells.
Llosa Matxalen, Schröder Gunnar, Dehio Christoph (2012), New perspectives into bacterial DNA transfer to human cells., in Trends in microbiology, 20(8), 355-9.
Persistence of Bartonella spp. stealth pathogens: from subclinical infections to vasoproliferative tumor formation.
Pulliainen Arto T, Dehio Christoph (2012), Persistence of Bartonella spp. stealth pathogens: from subclinical infections to vasoproliferative tumor formation., in FEMS microbiology reviews, 36(3), 563-99.
Persistence of Bartonella spp. stealth pathogens: from sub-clinical infections to vasoproliferative tumour formation
Pulliainen A. T., Dehio C. (2012), Persistence of Bartonella spp. stealth pathogens: from sub-clinical infections to vasoproliferative tumour formation, in FEMS Microbiol. Rev., 36(3), 563-599.
Persistent intracellular pathogens
Dehio Christoph, Berry Colin, Bartenschlager Ralf (2012), Persistent intracellular pathogens, in FEMS microbiology reviews, 36(3), 513-513.
Persistent intracellular pathogens.
Dehio Christoph, Berry Colin, Bartenschlager Ralf (2012), Persistent intracellular pathogens., in FEMS microbiology reviews, 36(3), 513-513.
Bartonella henselae engages inside-out and outside-in signaling by integrin β1 and talin1 during invasome-mediated bacterial uptake.
Truttmann Matthias C, Misselwitz Benjamin, Huser Sonja, Hardt Wolf-Dietrich, Critchley David R, Dehio Christoph (2011), Bartonella henselae engages inside-out and outside-in signaling by integrin β1 and talin1 during invasome-mediated bacterial uptake., in Journal of cell science, 124(Pt 21), 3591-602.
BID-F1 and BID-F2 domains of Bartonella henselae effector protein BepF trigger together with BepC the formation of invasome structures.
Truttmann Matthias C, Guye Patrick, Dehio Christoph (2011), BID-F1 and BID-F2 domains of Bartonella henselae effector protein BepF trigger together with BepC the formation of invasome structures., in PloS one, 6(10), 25106-25106.
Combined action of the type IV secretion effector proteins BepC and BepF promotes invasome formation of Bartonella henselae on endothelial and epithelial cells.
Truttmann Matthias C, Rhomberg Thomas A, Dehio Christoph (2011), Combined action of the type IV secretion effector proteins BepC and BepF promotes invasome formation of Bartonella henselae on endothelial and epithelial cells., in Cellular microbiology, 13(2), 284-99.
Combined MLST and AFLP typing of Bartonella henselae isolated from cats reveals new sequence types and suggests clonal evolution.
Mietze A, Morick D, Köhler H, Harrus S, Dehio C, Nolte I, Goethe R (2011), Combined MLST and AFLP typing of Bartonella henselae isolated from cats reveals new sequence types and suggests clonal evolution., in Veterinary microbiology, 148(2-4), 238-45.
Conjugative DNA transfer into human cells by the VirB/VirD4 type IV secretion system of the bacterial pathogen Bartonella henselae.
Schröder Gunnar, Schuelein Ralf, Quebatte Maxime, Dehio Christoph (2011), Conjugative DNA transfer into human cells by the VirB/VirD4 type IV secretion system of the bacterial pathogen Bartonella henselae., in Proceedings of the National Academy of Sciences of the United States of America, 108(35), 14643-8.
Fic domain-catalyzed adenylylation: insight provided by the structural analysis of the type IV secretion system effector BepA.
Palanivelu Dinesh V, Goepfert Arnaud, Meury Marcel, Guye Patrick, Dehio Christoph, Schirmer Tilman (2011), Fic domain-catalyzed adenylylation: insight provided by the structural analysis of the type IV secretion system effector BepA., in Protein science : a publication of the Protein Society, 20(3), 492-9.
Parallel evolution of a type IV secretion system in radiating lineages of the host-restricted bacterial pathogen Bartonella.
Engel Philipp, Salzburger Walter, Liesch Marius, Chang Chao-Chin, Maruyama Soichi, Lanz Christa, Calteau Alexandra, Lajus Aurélie, Médigue Claudine, Schuster Stephan C, Dehio Christoph (2011), Parallel evolution of a type IV secretion system in radiating lineages of the host-restricted bacterial pathogen Bartonella., in PLoS genetics, 7(2), 1001296-1001296.
The Bartonella henselae VirB/Bep system interferes with vascular endothelial growth factor (VEGF) signalling in human vascular endothelial cells.
Scheidegger Florine, Quebatte Maxime, Mistl Claudia, Dehio Christoph (2011), The Bartonella henselae VirB/Bep system interferes with vascular endothelial growth factor (VEGF) signalling in human vascular endothelial cells., in Cellular microbiology, 13(3), 419-31.
Transfer of R388 derivatives by a pathogenesis-associated type IV secretion system into both bacteria and human cells.
Fernández-González Esther, de Paz Héctor D, Alperi Anabel, Agúndez Leticia, Faustmann Marco, Sangari Félix J, Dehio Christoph, Llosa Matxalen (2011), Transfer of R388 derivatives by a pathogenesis-associated type IV secretion system into both bacteria and human cells., in Journal of bacteriology, 193(22), 6257-65.
Proteome-wide identification of predominant subcellular protein localizations in a bacterial model organism.
Stekhoven Daniel J, Omasits Ulrich, Quebatte Maxime, Dehio Christoph, Ahrens Christian H, Proteome-wide identification of predominant subcellular protein localizations in a bacterial model organism., in Journal of Proteomics.

Collaboration

Group / person Country
Types of collaboration
Departamento de Biología Molecular, Facultad Universidad de Cantabria, and Instituto de Biomedicina Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
University of Texas-Houston Medical School, Houston, Texas United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Institute of Molecular Systems Biology, ETH Zurich, Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Institut für Med. Mikrobio. und Krankenhaushyg., Universitätsklinikum Frankfurt am Main, Frankfurt Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Unité Sous Contrat Bartonella, INRA, Maisons-Alfort, France France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Institute for Experimental and Clinical Pharmacology and Toxicology, Universität Freiburg, Freiburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Gordon Research Conference "Microbial Adhesion & Signal Transduction" Talk given at a conference Probing the function of membrane-bound protein secretion machines 24.07.2013 Slave Regine University, Newport, United States of America Dehio Christoph;
European Workshop on Bacterial Protein Toxins (ETOX) 16 Talk given at a conference FIC domains in Bartonella:Evolution of diverse host effectors from a conserved bacterial toxin/antitoxin system 23.06.2013 University of Freiburg, Germany Dehio Christoph; Pieles Kathrin;
International Conference on Systems Biology of Human Disease (SBHD) 2013 Talk given at a conference International Conference on Systems Biology of Human Disease (SBHD) 13.06.2013 Heidelberg, Germany Dehio Christoph;
biology13 geht in den Zoo Talk given at a conference Organismische Biologie:Versuch einer Einordnung aus Sicht eines molekularen Infektionsbiologen 06.02.2013 University of Basel, Switzerland Dehio Christoph;
Microbiology Seminar Series Individual talk Type IV secretion systems: New insights into their evolution and function in bacterial pathogenesis 01.02.2013 University of Chicago, United States of America Dehio Christoph;
Multimédia Bactériens et Résistance Talk given at a conference Conjugative DNA transfer into human cells 05.12.2012 Paris, France Dehio Christoph;
Biophysical Aspects of Type IV Secretion Talk given at a conference Evolution and effector functions of Bartonella type IV secretion substrates 17.09.2012 Biobao, Spain Dehio Christoph;
ICAAC 2012 Talk given at a conference Conjugative DNA transfer into human cells 09.09.2012 San Francisco, United States of America Dehio Christoph;
Gordon Research Conference "Microbial Toxins & Pathogenicity" Talk given at a conference Evolution and effector functions of Bartonella type IV secretion substrates 08.07.2012 Waterville Valley, NH , United States of America Dehio Christoph;
EMBO Conference "Subversion of Host Cellular Organization and Functions by Pathogens" Talk given at a conference Systems-level analysis of Brucella cell entry, intracellular trafficking and replication 06.05.2012 Villars-sur-Ollon, Switzerland , Germany Dehio Christoph; Ben-Tekaya Houchaima;
7th International Conference on Bartonella as Animal and Human Pathogens Talk given at a conference Functional diversification of virulence-associated type IV secretion systems of the genus Bartonella 25.04.2012 Raleigh, North Carolina, United States of America Dehio Christoph;
External Seminar Series Individual talk Type IV secretion systems:New insights into their evolution and function in bacterial pathogenesis 01.02.2012 University of Munich, Germany Dehio Christoph;
FEMS Meeting 2011 Talk given at a conference Functional diversification of virulence-associated type IV secretion systems of the genus Bartonella 26.09.2011 Geneva, Switzerland, Switzerland Dehio Christoph;
IUMS 2011 Sapporo Talk given at a conference Functional diversification of virulence-associated type IV secretion systems of the genus Bartonella 06.09.2011 Sapporo, Japan Dehio Christoph;
Intracellular Niches and Trafficking during Host-Pathogen Interaction Talk given at a conference Role of type IV secretion systems in the pathogenesis of the facultative intracellular pathogenBartonella 13.05.2011 Erlangen, Deutschland, Germany Dehio Christoph;
SGM Spring Conference 2011 Talk given at a conference Role of type IV secretion systems in the intracellular lifestyleof Bartonella 11.04.2011 Harrogate, Great Britain and Northern Ireland Dehio Christoph;
Molekulare Mechanismen elementarer Lebensprozesse Talk given at a conference Role of type IV secretion systems in bacterial pathogenesis: The Bartonella paradigm 21.02.2011 Rostock, Germany Dehio Christoph;


Self-organised

Title Date Place
Molecular Aspects of Infectious Diseases 16.09.2011 Biozentrum, Universität Basel, Switzerland

Awards

Title Year
European Molecular Biology Organization (EMBO) membership 2013
Membership in the German National Academy of Sciences, Leopoldina 2010

Associated projects

Number Title Start Funding scheme
149886 Bacterial Type IV Secretion (T4S): Cellular, Molecular, and Evolutionary Basis of the Subversion of Host Cell Functions by Translocated Effector Proteins 01.10.2013 Project funding (Div. I-III)
109925 Modulation of host cell function by the bacterial type IV secretion process: molecular basis of the translocation and the intracellular effector function of secreted virulence factors 01.10.2005 Project funding (Div. I-III)

Abstract

Type IV secretion (T4S) systems of gram-negative bacteria are versatile nano-machines involved in many processes relevant to bacterial infection, such as horizontal transfer of virulence and antibiotic resistance genes between bacteria, and the translocation of bacterial effector proteins into eukaryotic target cells. Effector-translocating T4S systems are widely distributed among human pathogenic bacteria that cause mostly chronic infections, including Helicobacter pylori (causing gastritis and gastric cancer), Legionella pneumophila (causing Legionnaires disease), Bartonella spp. (causing bartonellosis) and Brucella spp. (causing brucellosis). In recent years we have - with support form the SNF (grants 3100-061777 and 31003A-109925) - established Bartonella as a powerful model for studying the cellular, molecular and evolutionary basis of T4S in bacterial pathogenesis. We have shown that the VirB T4S system represents an essential virulence device that translocates a cocktail of effector proteins (BepA-BepG) into human host cells, leading to the subversion of multiple cellular functions that facilitate chronic infection. We have characterized the secretion signal of these effector proteins, assigned physiological functions to individual effectors (such as anti-apoptosis to BepA) and defined molecular details of effector function (e.g. BepA-triggered elevation of cAMP leading to anti-apoptosis). By evolutionary genomic analysis we have further demonstrated that the VirB T4S system and its translocated Bep effectors facilitated the adaptation of the host-restricted bartonellae to novel hosts, thus contributing to the evolutionary success of these emerging zoonotic pathogens. In the frame of the proposed project we will continue to explore the paradigmatic Bartonella model of T4S. Moreover, we will expand the successful approach for studying T4S as established for Bartonella to the closely related pathogen Brucella - the etiological agent of the most important bacterial zoonosis worldwide that causes chronic infections in various mammals. We will apply a multidisciplinary experimental approach including bacterial genetics, cell biology, molecular biology, biochemistry, structural biology, genomics, and animal experimentation. In subproject A targeting T4S in Bartonella, we will perform a structure/function analysis of the VirB-translocated Bep effector proteins and their cellular targets, and study the molecular evolutionary mechanism of host adaptation mediated by these effectors. In subproject B targeting T4S in Brucella, we will focus on (i) a refined characterization of the VirB T4S system-dependent intracellular trafficking route of Brucella resulting in the establishment of an ER-derived bacterial replication niche, (ii) the systematic identification of host factors involved in this unique intracellular trafficking route, and (iii) a structure/function analysis of T4S effectors in interaction with the identified cellular targets. By studying the molecular mechanism of T4S in the closely related pathogens Bartonella and Brucella, we anticipate to provide major contributions to our knowledge how T4S facilitate chronic bacterial infections. Based on the specific subversion of multiple cellular functions by the T4S effectors of these pathogens we also expect to contribute new basic knowledge and novel tools to different fields of cell biology.
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