bacterial pathogenesis; immune response; type IV secretion ; bacterial effector protein; chronic infection; Bartonella; Brucella; animal infection model; Stat3
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.
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.
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.
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.
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.
Québatte Maxime, Dehio Christoph (2019), Bartonella gene transfer agent: Evolution, function, and proposed role in host adaptation., in Cellular microbiology
, 21(11), e13068.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Dehio Christoph, Bumann Dirk (2017), Editorial overview: Bacterial systems biology., in Current opinion in microbiology
, 39, viii-xi.
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.
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.
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.
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.
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.
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.