Bacterial Type IV Secretion (T4S): Cellular, Molecular and Evolutionary Basis of the Subversion of Host Cell Functions by Translocated Effector Proteins
Third-party funded project
Project title Bacterial Type IV Secretion (T4S): Cellular, Molecular and Evolutionary Basis of the Subversion of Host Cell Functions by Translocated Effector Proteins
Principal Investigator(s) Dehio, Christoph
Co-Investigator(s) Hiller Odermatt, Sebastian
Schirmer, Tilman
Stahlberg, Henning
Organisation / Research unit Faculty of Science,
Departement Biozentrum,
Departement Biozentrum / Infection Biology,
Departement Biozentrum / Molecular Microbiology (Dehio)
Project Website
Project start 01.04.2017
Probable end 31.03.2021
Status Active

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.

Keywords bacterial pathogenesis; immune response; type IV secretion ; bacterial effector protein; chronic infection; Bartonella; Brucella; animal infection model; Stat3
Financed by Swiss National Science Foundation (SNSF)
Follow-up project of 2190067 Bacterial Type IV Secretion (T4S): Cellular, Molecular, and Evolutionary Basis of the Subversion of Host Cell Functions by Translocated Effector Proteins

Published results ()

  ID Autor(en) Titel ISSN / ISBN Erschienen in Art der Publikation
4106892  Dehio, Christoph; Bumann, Dirk  Editorial overview: Bacterial systems biology  1879-0364  Current Opinion in Microbiology  JournalItem (Kommentare, Editorials, Rezensionen, Urteilsanmerk., etc. in einer wissensch. Zeitschr. 
4062191  Harms, Alexander; Segers, Francisca H. I. D.; Quebatte, Maxime; Mistl, Claudia; Manfredi, Pablo; Körner, Jonas; Chomel, Bruno B.; Kosoy, Michael; Maruyama, Soichi; Engel, Philipp; Dehio, Christoph  Evolutionary Dynamics of Pathoadaptation Revealed by Three Independent Acquisitions of the VirB/D4 Type IV Secretion System in Bartonella  1759-6653  Genome biology and evolution  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
4062206  Harms, Alexander; Liesch, Marius; Körner, Jonas; Québatte, Maxime; Engel, Philipp; Dehio, Christoph  A bacterial toxin-antitoxin module is the origin of inter-bacterial and inter-kingdom effectors of Bartonella  1553-7390 ; 1553-7404  PLoS Genetics  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
4398935  Sedzicki, Jaroslaw; Tschon, Therese; Low, Shyan Huey; Willemart, Kevin; Goldie, Kenneth N.; Letesson, Jean-Jacques; Stahlberg, Henning; Dehio, Christoph  3D correlative electron microscopy reveals continuity of Brucella -containing vacuoles with the endoplasmic reticulum  1477-9137  Journal of cell science  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
4487708  Lobet, Elodie; Willemart, Kevin; Ninane, Noëlle; Demazy, Catherine; Sedzicki, Jaroslaw; Lelubre, Christophe; De Bolle, Xavier; Renard, Patricia; Raes, Martine; Dehio, Christoph; Letesson, Jean-Jacques; Arnould, Thierry  Mitochondrial fragmentation affects neither the sensitivity to TNFα-induced apoptosis of Brucella-infected cells nor the intracellular replication of the bacteria  2045-2322  Scientific reports  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
4062208  Omasits, Ulrich; Varadarajan, Adithi R.; Schmid, Michael; Goetze, Sandra; Melidis, Damianos; Bourqui, Marc; Nikolayeva, Olga; Québatte, Maxime; Patrignani, Andrea; Dehio, Christoph; Frey, Juerg E.; Robinson, Mark D.; Wollscheid, Bernd; Ahrens, Christian H.  An integrative strategy to identify the entire protein coding potential of prokaryotic genomes by proteogenomics  1088-9051 ; 1549-5469  Genome Research  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
4062202  Québatte, Maxime; Dehio, Christoph  Systems-level interference strategies to decipher host factors involved in bacterial pathogen interaction: from RNAi to CRISPRi  1369-5274 ; 1879-0364  Current Opinion in Microbiology  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
4062199  Québatte, Maxime; Christen, Matthias; Harms, Alexander; Körner, Jonas; Christen, Beat; Dehio, Christoph  Gene Transfer Agent Promotes Evolvability within the Fittest Subpopulation of a Bacterial Pathogen  2405-4712 ; 2405-4720  Cell Systems  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
4062195  González-Prieto, Coral; Gabriel, Richard; Dehio, Christoph; Schmidt, Manfred; Llosa, Matxalen  The Conjugative Relaxase TrwC Promotes Integration of Foreign DNA in the Human Genome  0099-2240 ; 1098-5336  Applied and Environmental Microbiology  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 
3681269  Stanger, Frédéric V.; de Beer, Tjaart A. P.; Dranow, David M.; Schirmer, Tilman; Phan, Isabelle; Dehio, Christoph  The BID Domain of Type IV Secretion Substrates Forms a Conserved Four-Helix Bundle Topped with a Hook.  0969-2126 ; 1878-4186  Structure  Publication: JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift) 

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