Project

Back to overview

Bacterial Type IV Secretion (T4S): Cellular, Molecular, and Evolutionary Basis of the Subversion of Host Cell Functions by Translocated Effector Proteins

English title Bacterial Type IV Secretion (T4S): Cellular, Molecular, and Evolutionary Basis of the Subversion of Host Cell Functions by Translocated Effector Proteins
Applicant Dehio Christoph
Number 173119
Funding scheme Project funding (Div. I-III)
Research institution Biozentrum der Universität Basel
Institution of higher education University of Basel - BS
Main discipline Molecular Biology
Start/End 01.04.2017 - 31.03.2021
Approved amount 1'344'000.00
Show all

All Disciplines (8)

Discipline
Molecular Biology
Biophysics
Experimental Microbiology
Cellular Biology, Cytology
Genetics
Structural Research
Medical Microbiology
Biochemistry

Keywords (9)

bacterial pathogenesis; immune response; type IV secretion ; bacterial effector protein; chronic infection; Bartonella; Brucella; animal infection model; Stat3

Lay Summary (German)

Lead
Bakterielle Krankheitserreger injizieren oftmals sogenannte Effektorproteine in infizierte Wirtszellen. Das Projekt trägt dazu bei besser zu verstehen wie diese Effektorproteine gezielt die Physiologie infizierter Wirtszellen zum Vorteil der Erreger reprogrammieren.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Die nah verwandten bakteriellen Erreger Bartonella und Brucella verursachen chronische Infektionskrankheiten bei Mensch und Tier. Bedeutsam für die Infektionsprozesse dieser Krankheitskeime sind jeweils Effektorproteine - bakterielle Proteine die mit Hilfe einer molekularen Spritze - dem sogenannten Typ IV Sekretionsapparat - in infizierte Wirtszellen injiziert werden. Das Projekt trägt dazu bei auf molekularer Ebene zu verstehen wie diese Effektorproteine infizierte Wirtszellen zum Nutzen der Krankheitskeime manipulieren. Im Rahmen unserer bereits fortgeschrittenen Studien zu den Effektorproteinen von Bartonella werden wir detailliert deren Struktur-/Funktionsbeziehung in der Wechselwirkung mit Zielstrukturen in Zellen des Immunsystems untersuchen und deren Rolle bei der Manipulation der Immunantwort erforschen. Unsere jüngeren Studien zu den Effektorproteinen von Brucella zielen primär darauf ab deren Bedeutung für die intrazelluläre Lebensweise dieser Erreger besser zu verstehen. Hierbei gilt unser besonderes Augenmerk der Untersuchung wie Brucellen nach deren Aufnahme in Wirtszellen mit Hilfe dieser Effektorprotein ihre intrazelluläre Replikationsnische in einer speziellen Zellorganelle – dem sogenannten endoplasmatischen Retikulum - erreichen.

 

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Das Projekt umfasst Grundlagenforschung in einem medizinisch relevanten Kontext. Die Entschlüsselung der molekularen Wirkung von Effektorproteinen in infizierten Wirtszellen trägt bedeutsam zum Verständnis des bakteriellen Infektionsprozesses bei und könnte neue Ansatzpunkte für die Entwicklung innovativer Anti-Infektiva offenlegen.
Direct link to Lay Summary Last update: 07.06.2017

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Evolutionary Diversification of Host-Targeted Bartonella Effectors Proteins Derived from a Conserved FicTA Toxin-Antitoxin Module
Schirmer Tilman, de Beer Tjaart A. P., Tamegger Stefanie, Harms Alexander, Dietz Nikolaus, Dranow David M., Edwards Thomas E., Myler Peter J., Phan Isabelle, Dehio Christoph (2021), Evolutionary Diversification of Host-Targeted Bartonella Effectors Proteins Derived from a Conserved FicTA Toxin-Antitoxin Module, in Microorganisms, 9(8), 1645-1645.
Structural basis for selective AMPylation of Rac-subfamily GTPases by Bartonella effector protein 1 (Bep1)
Dietz Nikolaus, Huber Markus, Sorg Isabel, Goepfert Arnaud, Harms Alexander, Schirmer Tilman, Dehio Christoph (2021), Structural basis for selective AMPylation of Rac-subfamily GTPases by Bartonella effector protein 1 (Bep1), in Proceedings of the National Academy of Sciences, 118(12), e202324511-e202324511.
Bartonella effector protein C mediates actin stress fiber formation via recruitment of GEF-H1 to the plasma membrane
Marlaire Simon, Dehio Christoph (2021), Bartonella effector protein C mediates actin stress fiber formation via recruitment of GEF-H1 to the plasma membrane, in PLOS Pathogens, 17(1), e1008548-e1008548.
A Bartonella Effector Acts as Signaling Hub for Intrinsic STAT3 Activation to Trigger Anti-inflammatory Responses
Sorg Isabel, Schmutz Christoph, Lu Yun-Yueh, Fromm Katja, Siewert Lena K., Bögli Alexandra, Strack Kathrin, Harms Alexander, Dehio Christoph (2020), A Bartonella Effector Acts as Signaling Hub for Intrinsic STAT3 Activation to Trigger Anti-inflammatory Responses, in Cell Host & Microbe, 27(3), 476-485.e7.
PyBDA: a command line tool for automated analysis of big biological data sets
Dirmeier Simon, Emmenlauer Mario, Dehio Christoph, Beerenwinkel Niko (2019), PyBDA: a command line tool for automated analysis of big biological data sets, in BMC Bioinformatics, 20(1), 564-564.
Bartonella gene transfer agent: Evolution, function, and proposed role in host adaptation.
Québatte Maxime, Dehio Christoph (2019), Bartonella gene transfer agent: Evolution, function, and proposed role in host adaptation., in Cellular microbiology, 21(11), e13068.
Definitions and guidelines for research on antibiotic persistence.
Balaban NQ, Helaine S, Lewis K, Ackermann M, Aldridge B, Andersson DI, Brynildsen MP, Bumann D, Camilli A, Collins JJ, Dehio C, Fortune S, Ghigo JM, Zinkernagel A (2019), Definitions and guidelines for research on antibiotic persistence., in Nature reviews. Microbiology, 17(7), 441-448.
A Role for the VPS Retromer in Brucella Intracellular Replication Revealed by Genomewide siRNA Screening.
Casanova Alain, Low Shen-Huay, Québatte Maxime, Sedzicki Jaroslaw, Tschon Therese, Ketterer Maren, Smith Kevin, Emmenlauer Mario, Ben-Tekaya Houchaima, Dehio Christoph (2019), A Role for the VPS Retromer in Brucella Intracellular Replication Revealed by Genomewide siRNA Screening., in mSphere, 4(3), pii: e0038.
Versatility of the BID Domain: Conserved Function as Type-IV-Secretion-Signal and Secondarily Evolved Effector Functions Within Bartonella-Infected Host Cells.
Wagner A, Tittes C, Dehio C (2019), Versatility of the BID Domain: Conserved Function as Type-IV-Secretion-Signal and Secondarily Evolved Effector Functions Within Bartonella-Infected Host Cells., in Frontiers in microbiology, 10(921), 1-7.
Quantitative contribution of efflux to multi-drug resistance of clinical Escherichia coli and Pseudomonas aeruginosa strains.
Cunrath O, Meinel DM, Maturana P, Fanous J, Buyck JM, Saint Auguste P, Seth-Smith HMB, Körner J, C Dehio, Trebosc V, Kemmer C, Neher R, Egli A, Bumann D (2019), Quantitative contribution of efflux to multi-drug resistance of clinical Escherichia coli and Pseudomonas aeruginosa strains., in EBioMedicine, 41, 479-487.
Role of distinct type-IV-secretion systems and secreted effector sets in host adaptation by pathogenic Bartonella species.
Wagner Alexander, Dehio Christoph (2019), Role of distinct type-IV-secretion systems and secreted effector sets in host adaptation by pathogenic Bartonella species., in Cellular microbiology, 21(3), e13004.
Multi-omic measurements of heterogeneity in HeLa cells across laboratories.
Bena FS, Zhou h, Dehio C, Testa G, Saez-Rodriguez J, Antonarakis SE, Hardt WD, Aebersold R, Liu Y, Mi Y, Mueller T, Kreibich S, Williams EG, Van Drogen A, Borel C, Frank M, Germain PL, Bludau I, Mehnert M, Seifert M, Emmenlauer M, Sorg I, Bezrukov F (2019), Multi-omic measurements of heterogeneity in HeLa cells across laboratories., in Nature biotechnology, 37(3), 314-322.
Growth-restricting effects of siRNA transfections: a largely deterministic combination of off-target binding and hybridization-independent competition.
Daga N, Eicher S, Kannan A, Casanova A, Low SH, Kreibich S, Andritschke D, Emmenlauer M, Jenkins JL, Hardt WD, Greber UF, Dehio C, von Mering C (2018), Growth-restricting effects of siRNA transfections: a largely deterministic combination of off-target binding and hybridization-independent competition., in Nucleic acids research, 46(18), 9309-9320.
Improved pathway reconstruction from RNA interference screens by exploiting off-target effects.
Srivatsa Sumana, Kuipers Jack, Schmich Fabian, Eicher Simone, Emmenlauer Mario, Dehio Christoph, Beerenwinkel Niko (2018), Improved pathway reconstruction from RNA interference screens by exploiting off-target effects., in Bioinformatics (Oxford, England), 34(13), i519-i527.
Mitochondrial fragmentation affects neither the sensitivity to TNFα-induced apoptosis of Brucella-infected cells nor the intracellular replication of the bacteria.
Lobet Elodie, Willemart Kevin, Ninane Noelle, Demazy Catherine, Sedzicki Jaroslaw, Lelubre Christophe, De Bolle Xavier, Renard Patricia, Raes Martine, Dehio Christoph, Letesson Jean-Jacques, Arnould Thierry (2018), Mitochondrial fragmentation affects neither the sensitivity to TNFα-induced apoptosis of Brucella-infected cells nor the intracellular replication of the bacteria., in Scientific reports, 8(1), 5173.
3D correlative electron microscopy reveals continuity of Brucella-containing vacuoles with the endoplasmic reticulum.
Sedzicki Jaroslaw, Tschon Therese, Low Shen Huay, Willemart K, Goldie KN, Letesson Jean-Jaques, Stahlberg Henning, Dehio Christoph (2018), 3D correlative electron microscopy reveals continuity of Brucella-containing vacuoles with the endoplasmic reticulum., in Journal of cell science, 131(4), 1-11.
An integrative strategy to identify the entire protein coding potential of prokaryotic genomes by proteogenomics.
Omasits U, Varadarajan AR, Schmid M, Goetze S, Melidis D, Bourqui M, Nikolayeva O, Québatte M, Patrignani A, Dehio C, Frey JE, Robinson MD, Ahrens CH (2017), An integrative strategy to identify the entire protein coding potential of prokaryotic genomes by proteogenomics., in Genome research, 27(12), 2083-2095.
A bacterial toxin-antitoxin module is the origin of inter-bacterial and inter-kingdom effectors of Bartonella.
Harms Alexander, Liesch Marius, Körner Jonas, Québatte Maxime, Engel Philipp, Dehio Christoph (2017), A bacterial toxin-antitoxin module is the origin of inter-bacterial and inter-kingdom effectors of Bartonella., in PLoS genetics, 13(10), :e1007077.
Editorial overview: Bacterial systems biology.
Dehio Christoph, Bumann Dirk (2017), Editorial overview: Bacterial systems biology., in Current opinion in microbiology, 39, viii-xi.
Systems-level interference strategies to decipher host factors involved in bacterial pathogen interaction: from RNAi to CRISPRi.
Québatte Maxime, Dehio Christoph (2017), Systems-level interference strategies to decipher host factors involved in bacterial pathogen interaction: from RNAi to CRISPRi., in Current opinion in microbiology, 39, 34-41.
Gene Transfer Agent Promotes Evolvability within the Fittest Subpopulation of a Bacterial Pathogen.
Québatte M, Christen M, Harms A, Körner J, Christen B, Dehio C (2017), Gene Transfer Agent Promotes Evolvability within the Fittest Subpopulation of a Bacterial Pathogen., in Cell systems, 4(6), 611-621.
The Conjugative Relaxase TrwC Promotes Integration of Foreign DNA in the Human Genome
González-Prieto C, Gabriel R, Dehio C, Schmidt M, Llosa M (2017), The Conjugative Relaxase TrwC Promotes Integration of Foreign DNA in the Human Genome, in Applied and environmental microbiology, 83(12), e00207-d00217.
Evolutionary Dynamics of Pathoadaptation Revealed by Three Independent Acquisitions of the VirB/D4 Type IV Secretion System in Bartonella.
Harms A, Segers FH, Quebatte M, Mistl C, Manfredi P, Körner J, Chomel BB, Kosoy M, Maruyama S, Engel P, Dehio C (2017), Evolutionary Dynamics of Pathoadaptation Revealed by Three Independent Acquisitions of the VirB/D4 Type IV Secretion System in Bartonella., in Genome biology and evolution, 9(3), 761-776.
Explicit Modeling of siRNA-Dependent On- and Off-Target Repression Improves the Interpretation of Screening Results.
Riba A, Emmenlauer M, Chen A, Sigoillot F, Cong F, Dehio C, Jenkins J, Zavolan M (2017), Explicit Modeling of siRNA-Dependent On- and Off-Target Repression Improves the Interpretation of Screening Results., in Cell systems, 4(2), 182-193.

Collaboration

Group / person Country
Types of collaboration
Jean-Jacques Letesson/University of Namur Belgium (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Tilman Schirmer/Biozentrum Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Tierry Arnold/University of Namur Belgium (Europe)
- Publication
Jean Celli/University of California at Davis United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
LOEWE CENTER DRUID, Spring Symposium (online) Talk given at a conference Hemotropic Infection by the BacterialPathogen Bartonella is Controlled byNeutralizing Antibodies 22.02.2021 Langen, Germany, Germany Dehio Christoph;
AMPylationPlus virtual conference Talk given at a conference The FIC protein ‘Bartonella effector protein C’ triggers actin stress fiber formation by a non-enzymatic mechanism 08.07.2020 virtual, United States of America Dehio Christoph;
Gordon Research Conference "Microbial Adhesion and Signal Transduction" Talk given at a conference Bartonella Effectors Targeting Innate Immune Signaling 21.07.2019 Newport/Rhode Island, United States of America Dehio Christoph;
EMBO Workshop "Toxin-antitoxin systems in bacteria Talk given at a conference FicTA modules: Bi-functional enzymes mediating intra-bacterial, inter-bacterial and inter-kingdom PTMs 15.04.2019 Windsor, Great Britain and Northern Ireland Dehio Christoph;
UNIA Workshop "Contribution of bacterial injection systems to human disease" Talk given at a conference Evolutionary and structure-function analysis of T4SS effector of Bartonella 05.11.2018 Baeza, Spain Dehio Christoph;
9th International Conference on Bartonella as Emerging Pathogens Talk given at a conference Evolutionary and structure-function analysis of Bartonella effector proteins 18.09.2018 Paris, France Dehio Christoph;
InfectoOptics - Life meets Light Talk given at a conference New insights into the intracellular life style of the zoonotic pathogen Brucella 05.09.2018 Jena, Germany Dehio Christoph;
EMBO | EMBL Symposium: Innate Immunity in Host-Pathogen Interactions Talk given at a conference Bartonella inhibits pro-inflammatory signaling by non-canonical STAT3 activation 24.06.2018 Heidelberg, Germany Dehio Christoph;
8th International Conference on Bartonella Emerging Pathogens Talk given at a conference Evolution and function of type IV secretion effectors in Bartonella 10.10.2017 Beijing, China Dehio Christoph;
EMBO | EMBL Symposium: New Approaches and Concepts in Microbiology Talk given at a conference Gene transfer agent and bacterial pathogenesis 27.06.2017 Heidelberg, Germany Dehio Christoph;


Self-organised

Title Date Place
European Workshop on Bacterial Protein Toxins 22.06.2019 Davos, Switzerland
Gordon Research Conference "Microbial Adhesion and Signal Transduction" 23.07.2017 Newport/Rhode Island, United States of America

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Symposium Antibiotikaresistenz Talk 14.11.2017 Bern, Switzerland Dehio Christoph;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Mikroben unter uns... „Catch me if you can: Wie Bakterien das Immunsystem austricksen“ German-speaking Switzerland 2019

Associated projects

Number Title Start Funding scheme
201273 Bacterial Type IV Secretion (T4S): Cellular, Molecular, and Evolutionary Basis of the Subversion of Host Cell Functions by Translocated Effector Proteins 01.04.2021 Project funding (Div. I-III)
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)

Abstract

The type IV secretion (T4S) systems of Gram-negative bacteria are versatile nanomachines ancestrally related to bacterial conjugation systems. Numerous bacterial pathogens targeting eukaryotic host cells have adopted these supramolecular protein assemblies for the intracellular delivery of bacterial effector proteins from the bacterial cytoplasm directly into the host cell cytoplasm. We are using zoonotic pathogens belonging to the closely related genus Bartonella (causing bartonellosis) and Brucella (causing brucellosis) to address fundamental questions related to the roles of T4S systems and their effector proteins in the establishment of chronic bacterial infection.Over the past 16 years we have - with support from the SNSF (grants 61777, 109925, 132979, and 149886) - established Bartonella as a powerful model for studying the cellular, molecular and evolutionary basis of T4S in bacterial pathogenesis. In early studies we have shown that the VirB T4S system represents an essential virulence device that translocates a cocktail of Bartonella effector proteins (Beps) into mammalian host cells, which subverts multiple cellular functions that facilitate chronic infection. We have then functionally characterized the bipartite secretion signal of Beps composed of a C-terminal BID domain and a charged tail. In recent years, we have assigned physiological functions to several Beps, identified some of their host cellular targets and performed corresponding structure-function analysis. We have also shown that all Beps are derived from a single ancestral effector that resulted from the fusion of a FIC domain derived from a bacterial toxin-antitoxin system that mediates AMPylation of target proteins and a BID domain derived from the secreted substrate (relaxase) of a conjugation system. We have further shown that independent Bep arsenals evolved in parallel in three Bartonella sublineages by gene duplication and diversification events, eventually resulting in Bep arsenals that facilitated adaptation of the host-restricted bartonellae to novel mammalian hosts. In the frame of the proposed project (subproject A), we want to deepen our understanding of the molecular functions of representatives of the growing repertoire of Beps by identifying their host targets and performing molecular and structure-function analysis. A major goal will be to understand the functional versatility of the limited set of Bep effector domains - FIC, BID and phosphorylated tyrosine arrays - to subvert a wide spectrum of host functions. Moreover, we want to characterize the physiological functions of representative Beps during infection using cell culture and animal infection models, with a focus of understanding how they facilitate evasion of innate immune responses by the pathogen and support bacterial spreading from the dermal infection site towards the replicative niches in deep tissues and blood.The Brucella project - funded by SNSF grants 132979 and 149886 - was initiated six years ago as a new research line. We are studying the role of the T4S system and its effectors in trafficking of the Brucella containing vacuole (BCV) and the establishment of an intracellular replication niche in the endoplasmic reticulum (ER). We have shown that the T4S system-dependent escape of the early BCV from the degradative endocytic network and its trafficking towards the ER depends on retrograde endosome-to-Golgi trafficking pathways. Moreover, using yeast as surrogate model we have been able to map the wiring of T4S effectors to conserved eukaryotic signaling and trafficking pathways and we identified candidates of some of their mammalian target proteins by yeast two-hybrid screens. In the frame of the proposed project (subproject B) we intend to (i) refine our understanding of the T4S-dependent intracellular trafficking route of the BCV towards the replicative niche in the ER and (ii) study the molecular functions of individual T4S effectors in this process. Due to the small size of the biosafety 3 (BSL3) laboratory presently used by us at the nearby Swiss TPH Institute this project will remain a rather small activity and limited to cell culture infection models until 2018 when we will move into the new Biozentrum building with its state-of-the-art BSL3 facility that will allow us to significantly expand our activities in this project, including animal experimentation.
-