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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 149886
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 01.10.2013 - 30.09.2016
Approved amount 901'639.00
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All Disciplines (6)

Discipline
Molecular Biology
Biochemistry
Medical Microbiology
Cellular Biology, Cytology
Genetics
Experimental Microbiology

Keywords (9)

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

Lay Summary (German)

Lead
Verschiedenartige bakterielle Erreger manipulieren wichtige Funktionen ihrer Wirtszellen mit Hilfe von Effektorproteinen, die durch eine spezifische Nanomaschine, das Typ IV Sekretionssystem (T4SS), eingespritzt werden. Zum besseren Verständnis der zellulären, molekularen und evolutionären Basis der Umsteuerung zellulärer Funktionen durch T4SS-translozierte Effektorproteine bei der Etablierung chronischer Infektionen untersuchen wir beispielhaft die zoonotischen Erreger Bartonella und Brucella.
Lay summary

Während der initialen Förderphase des SNF Grants 31003A-132979 (10/2010 - 09/2013) haben wir zur Untersuchung der molekularen Funktionen von T4SS und hiervon translozierten Effektorproteinen von  Bartonella and Brucella hinsichtlich der gezielten Umsteuerung von Wirtszellfunktionen einen multidisziplinären Experimentalansatz verfolgt, der Bakteriengenetik, Zellbiologie, Molekularbiologie, Biochemie, Strukturbiologie, Genomik and experimentelle Pathologie umfasste. Für die 3-jährige Verlängerungsperiode (10/2013-09/2016) werden wir diesen etablierten Experimentalansatz durch das Hefe-Modellsystem ergänzen, mit dessen Hilfe insbesondere konservierte eukaryontische Signalwege untersucht werden sollen, die von T4SS-Effektorproteinen manipuliert werden. Subprojekt A umfasst die Struktur/Funktionsuntersuchung der durch das VirB T4SS von Bartonella translozierten Bep (Bartonella effector proteins) Effektorproteine und deren physiologische Konsequenzen für die Wirtszelle, insbesondere hinsichtlich der Manipulation von Signalketten der Immunantwort. Subproject B umfasst die Struktur/Funktionsuntersuchung der durch das VirB T4SS von Brucella translozierten Effektorproteine und deren physiologische Konsequenzen für die Wirtszellinteraktion, insbesondere hinsichtlich des umgesteuerten zellulären Transports der es den Bakterien erlaubt ihre  Replikationsnische in einem spezifischen Membrankompartiment mit Charakteristika des endoplasmatischen Reticulums zu erreichen. Diese Untersuchungen sollen exemplarisch die Rolle von T4SS Effektoren bei der Etablierung chronischer Infektionen beleuchten, könnten aber auch zur Entwicklung neuartiger Strategien zur Behandlung des zugrunde liegenden Infektionsgeschehens beitragen. Aufgrund der spezifischen Manipulation mannigfaltiger zellulärer Funktionen durch T4SS Effektoren erwarten wir weiterhin neues Grundlagenwissen und neue Werkzeuge zur Untersuchung zellbiologischer Prozesse zu schaffen.

Direct link to Lay Summary Last update: 30.10.2013

Lay Summary (English)

Lead
Several bacterial pathogens that cause chronic infections in mammals manipulate host cellular functions by specific effector proteins injected via a dedicated nano-machine, the type IV secretion (T4S) system. We are using the related zoonotic pathogens Bartonella spp. and Brucella spp. as models to study the cellular, molecular and evolutionary basis of the subversion of host cell functions by T4S-translocated effector proteins in the course of establishing chronic infection.
Lay summary

In the initial funding period of the SNSF grant 31003A-132979 (10/2010-09/2013) we used a multidisciplinary experimental approach, including bacterial genetics, cell biology, molecular biology, biochemistry, structural biology, genomics, and animal experimentation in order to study the molecular function of T4S systems and their translocated effector proteins in Bartonella and Brucella in manipulationg host cellular functions to the benefit of the pathogen. For the three year prolongation period (10/2013-09/2016) the established multidisciplinary experimental approach will be extended by adopting yeast as surrogate model for studying conserved eukaryotic processes targeted by T4S effectors. Subproject A will focus on the structure/function analysis of Bartonella effector proteins (Beps) translocated by the VirB T4S system of Bartonella and their physiological consequences on the host, with particular emphasis on studying the subversion of immune signaling processes. Subproject B will focus on the functional analysis of effector proteins translocated by the distinct VirB T4S system of Brucella and their physiological consequences on host cell interaction, with particular emphasis on studying the intracellular trafficking events that allow the bacteria to reach their replication niche in a unique membrane compartment displaying molecular characteristics of the endoplasmic reticulum. Together, these studies will contribute to establishing a molecular paradigm for the role of T4S effectors in triggering chronic bacterial infection, which may also help to design novel strategies to combat bacterial virulence. Based on the specific manipulation 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: 30.10.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
A Genome-Wide siRNA Screen Implicates Spire1/2 in SipA-Driven Salmonella Typhimurium Host Cell Invasion.
Andritschke Daniel, Dilling Sabrina, Emmenlauer Mario, Welz Tobias, Schmich Fabian, Misselwitz Benjamin, Rämö Pauli, Rottner Klemens, Kerkhoff Eugen, Wada Teiji, Penninger Josef M, Beerenwinkel Niko, Horvath Peter, Dehio Christoph, Hardt Wolf-Dietrich (2016), A Genome-Wide siRNA Screen Implicates Spire1/2 in SipA-Driven Salmonella Typhimurium Host Cell Invasion., in PloS one, 11(9), 0161965-0161965.
Biological Diversity and Molecular Plasticity of FIC Domain Proteins.
Harms Alexander, Stanger Frédéric V, Dehio Christoph (2016), Biological Diversity and Molecular Plasticity of FIC Domain Proteins., in Annual review of microbiology, 70, 341-60.
Crystal Structure of the Escherichia coli Fic Toxin-Like Protein in Complex with Its Cognate Antitoxin.
Stanger Frédéric V, Harms Alexander, Dehio Christoph, Schirmer Tilman (2016), Crystal Structure of the Escherichia coli Fic Toxin-Like Protein in Complex with Its Cognate Antitoxin., in PloS one, 11(9), 0163654-0163654.
Intrinsic regulation of FIC-domain AMP-transferases by oligomerization and automodification.
Stanger Frédéric V, Burmann Björn M, Harms Alexander, Aragão Hugo, Mazur Adam, Sharpe Timothy, Dehio Christoph, Hiller Sebastian, Schirmer Tilman (2016), Intrinsic regulation of FIC-domain AMP-transferases by oligomerization and automodification., in Proceedings of the National Academy of Sciences of the United States of America, 113(5), 529-37.
Microscopy-based Assays for High-throughput Screening of Host Factors Involved in Brucella Infection of Hela Cells.
Casanova Alain, Low Shyan H, Emmenlauer Mario, Conde-Alvarez Raquel, Salcedo Suzana P, Gorvel Jean-Pierre, Dehio Christoph (2016), Microscopy-based Assays for High-throughput Screening of Host Factors Involved in Brucella Infection of Hela Cells., in Journal of visualized experiments : JoVE, (114), 1.
Adenylylation of Gyrase and Topo IV by FicT Toxins Disrupts Bacterial DNA Topology.
Harms Alexander, Stanger Frédéric Valentin, Scheu Patrick Daniel, de Jong Imke Greet, Goepfert Arnaud, Glatter Timo, Gerdes Kenn, Schirmer Tilman, Dehio Christoph (2015), Adenylylation of Gyrase and Topo IV by FicT Toxins Disrupts Bacterial DNA Topology., in Cell reports, 12(9), 1497-507.
Autophagy Proteins Promote Repair of Endosomal Membranes Damaged by the Salmonella Type Three Secretion System 1.
Kreibich Saskia, Emmenlauer Mario, Fredlund Jennifer, Rämö Pauli, Münz Christian, Dehio Christoph, Enninga Jost, Hardt Wolf-Dietrich (2015), Autophagy Proteins Promote Repair of Endosomal Membranes Damaged by the Salmonella Type Three Secretion System 1., in Cell host & microbe, 18(5), 527-37.
Genome-Wide siRNA Screen Identifies Complementary Signaling Pathways Involved in Listeria Infection and Reveals Different Actin Nucleation Mechanisms during Listeria Cell Invasion and Actin Comet Tail Formation.
Kühbacher Andreas, Emmenlauer Mario, Rämo Pauli, Kafai Natasha, Dehio Christoph, Cossart Pascale, Pizarro-Cerdá Javier (2015), Genome-Wide siRNA Screen Identifies Complementary Signaling Pathways Involved in Listeria Infection and Reveals Different Actin Nucleation Mechanisms during Listeria Cell Invasion and Actin Comet Tail Formation., in mBio, 6(3), 00598-15.
gespeR: a statistical model for deconvoluting off-target-confounded RNA interference screens.
Schmich Fabian, Szczurek Ewa, Kreibich Saskia, Dilling Sabrina, Andritschke Daniel, Casanova Alain, Low Shyan Huey, Eicher Simone, Muntwiler Simone, Emmenlauer Mario, Rämö Pauli, Conde-Alvarez Raquel, von Mering Christian, Hardt Wolf-Dietrich, Dehio Christoph, Beerenwinkel Niko (2015), gespeR: a statistical model for deconvoluting off-target-confounded RNA interference screens., in Genome biology, 16, 220-220.
NEMix: single-cell nested effects models for probabilistic pathway stimulation.
Siebourg-Polster Juliane, Mudrak Daria, Emmenlauer Mario, Rämö Pauli, Dehio Christoph, Greber Urs, Fröhlich Holger, Beerenwinkel Niko (2015), NEMix: single-cell nested effects models for probabilistic pathway stimulation., in PLoS computational biology, 11(4), 1004078-1004078.
New insights into the role of Bartonella effector proteins in pathogenesis.
Siamer Sabrina, Dehio Christoph (2015), New insights into the role of Bartonella effector proteins in pathogenesis., in Current opinion in microbiology, 23, 80-5.
A translocated effector required for Bartonella dissemination from derma to blood safeguards migratory host cells from damage by co-translocated effectors.
Okujava Rusudan, Guye Patrick, Lu Yun-Yueh, Mistl Claudia, Polus Florine, Vayssier-Taussat Muriel, Halin Cornelia, Rolink Antonius G, Dehio Christoph (2014), A translocated effector required for Bartonella dissemination from derma to blood safeguards migratory host cells from damage by co-translocated effectors., in PLoS pathogens, 10(6), 1004187-1004187.
An experimental strategy for the identification of AMPylation targets from complex protein samples.
Pieles Kathrin, Glatter Timo, Harms Alexander, Schmidt Alexander, Dehio Christoph (2014), An experimental strategy for the identification of AMPylation targets from complex protein samples., in Proteomics, 14(9), 1048-52.
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 (2014), Proteome-wide identification of predominant subcellular protein localizations in a bacterial model organism., in Journal of proteomics, 99, 123-37.
Simultaneous analysis of large-scale RNAi screens for pathogen entry.
Rämö Pauli, Drewek Anna, Arrieumerlou Cécile, Beerenwinkel Niko, Ben-Tekaya Houchaima, Cardel Bettina, Casanova Alain, Conde-Alvarez Raquel, Cossart Pascale, Csúcs Gábor, Eicher Simone, Emmenlauer Mario, Greber Urs, Hardt Wolf-Dietrich, Helenius Ari, Kasper Christoph, Kaufmann Andreas, Kreibich Saskia, Kühbacher Andreas, Kunszt Peter, Low Shyan Huey, Mercer Jason, Mudrak Daria, Muntwiler Simone, Pelkmans Lucas (2014), Simultaneous analysis of large-scale RNAi screens for pathogen entry., in BMC genomics, 15, 1162-1162.
Specific inhibition of diverse pathogens in human cells by synthetic microRNA-like oligonucleotides inferred from RNAi screens.
Franceschini Andrea, Meier Roger, Casanova Alain, Kreibich Saskia, Daga Neha, Andritschke Daniel, Dilling Sabrina, Rämö Pauli, Emmenlauer Mario, Kaufmann Andreas, Conde-Álvarez Raquel, Low Shyan Huey, Pelkmans Lucas, Helenius Ari, Hardt Wolf-Dietrich, Dehio Christoph, von Mering Christian (2014), Specific inhibition of diverse pathogens in human cells by synthetic microRNA-like oligonucleotides inferred from RNAi screens., in Proceedings of the National Academy of Sciences of the United States of America, 111(12), 4548-53.
Structure of the N-terminal Gyrase B fragment in complex with ADP⋅Pi reveals rigid-body motion induced by ATP hydrolysis.
Stanger Frédéric V, Dehio Christoph, Schirmer Tilman (2014), Structure of the N-terminal Gyrase B fragment in complex with ADP⋅Pi reveals rigid-body motion induced by ATP hydrolysis., in PloS one, 9(9), 107289-107289.
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.
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.
Imaging InlC secretion to investigate cellular infection by the bacterial pathogen Listeria monocytogenes.
Kühbacher Andreas, Gouin Edith, Mercer Jason, Emmenlauer Mario, Dehio Christoph, Cossart Pascale, Pizarro-Cerdá Javier (2013), Imaging InlC secretion to investigate cellular infection by the bacterial pathogen Listeria monocytogenes., in Journal of visualized experiments : JoVE, (79), 51043-51043.
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.
The BID Domain of Type IV Secretion Substrates Forms a Conserved Four-Helix Bundle Topped with a Hook.
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., in Structure (London, England : 1993).

Collaboration

Group / person Country
Types of collaboration
Prof. Tilman Schirmer/Biozentrum, Universität Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Xavier de Bolle/Facultés Universitaires Notre-Dame de la Paix (FUNDP), Namur Belgium (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Jean-Pierre Gorvel France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Sebastian Hiller Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Wolf-Dietrich Hardt Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Matxalen Lllosa Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Kenn Gerdes Denmark (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Antonius Rolink/Department Biomedizin, Universität Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Seminar at Institut de Microbiologie de la Méditerranée CNRS - Aix-Marseille Université Individual talk Structure/function and evolutionary analysis of bacterial effectors subverting host cell signaling 16.09.2016 Aix-Marseille Université, Marseille, France Dehio Christoph;
Seminar at Swiss Tropical and Public Health Institute Individual talk Function and evolutionary origin of Bartonella effectors subverting host cell signaling 25.05.2016 Swiss TPH, Basel, Switzerland Dehio Christoph;
Seminar at University of Geneva Individual talk Evolution of diversified host-targeted effectors from a widely-spread bacterial toxin/antitoxin system 15.02.2016 University of Geneva, Geneva, Switzerland Dehio Christoph;
Seminar at IBMC Individual talk Function and evolutionary origin of bacterial effectors subverting host cell function 11.12.2015 IBMC, Porto, Portugal Dehio Christoph;
CSH Asia Conference Bacterial Infection and Host Defense Talk given at a conference FIC domains in Bartonella: Evolution of diverse host effectors from a widely-spread bacteria toxin-antitoxin system 02.11.2015 Suzhou, China Dehio Christoph;
Seminar at University of Lausanne Individual talk Function and evolutionary origin of bacterial effectors subverting host cell signaling 23.10.2015 University of Lausanne, Lausanne, Switzerland Dehio Christoph;
2015 NextGen Genomics, Biology, Bioinformatics and Technologies (NGBT) Conference Talk given at a conference Dealing with off-target effects in large-scale RNAi screens 01.10.2015 HICC, Hyderabad, India Dehio Christoph;
Seminar at Institut Pasteur Individual talk Function and evolutionary origin of bacterial effectors subverting host cell function 17.06.2015 Institut Pasteur, Paris, France Dehio Christoph;
ESCCAR International Congress on Rickettsia and other Intracellular Bacteria, held in Lausanne, Switzerland Talk given at a conference Control of immune functions by a Bartonella T4SS effector 13.06.2015 CHUV, Lausanne, Switzerland Dehio Christoph;
6th Congress of European Microbiologists Talk given at a conference Evolution of Bartonella type IV secretion effectors from a widely-spread toxin/antitoxin system 07.06.2015 Mastricht, Netherlands Dehio Christoph;
Seminar at EPFL Individual talk Function and evolutionary origin of bacterial effectors subverting host cell signalling 29.05.2015 EPFL, Lausanne, Switzerland Dehio Christoph;
11e CONGRES NATIONAL DE LA SFM Talk given at a conference Control of innate immune functions by bacterial effectors: Lessons learned from Bartonella 23.03.2015 Institut Pasteur, Paris, France Dehio Christoph;
Symposium - Equipex ImaginEx BioMed Light Electron Atomic force microscopies Days Talk given at a conference High-content siRNA screen for cell entry, trafficking and replication of Brucella abortus 26.11.2014 Lille, Belgium Dehio Christoph;
Seminar am Institut für Medizinische Mikrobiologie Individual talk FIC domains in Bartonella: Evolution of diverse host effectors from a widely-spread bacteria toxin-antitoxin system 13.11.2014 University of Zurich, Zurich, Switzerland Dehio Christoph;
Seminar at University of Oxford Individual talk Type IV secretion systems: New insights into their evolution and function in bacterial pathogenesis 11.11.2014 University of Oxford, UK, United States of America Dehio Christoph;
The 50th Anniversary EMBO Members' Meeting 2014 Talk given at a conference Role of protein AMPylation by the pervasive FIC domain 29.10.2014 The 50th Anniversary EMBO Members' Meeting 2014, Germany Dehio Christoph;
4. Gemeinsame Jahrestagung der DGHM und VAAM Talk given at a conference Evolution of Bartonella type IV secretion effectors from a widely-spread toxin/antitoxin system 05.08.2014 Dresden, Germany Dehio Christoph;
Seminar Center for Infectious Disease Research, University of Würzburg, Germany Individual talk FIC domains in Bartonella: Evolution of diverse host effectors from a widely-spread bacteria toxin-antitoxin system 14.07.2014 Würzburg, Germany Dehio Christoph;
Biozentrum In-house seminar series Individual talk Systems-level analysis of the bacterial infection process 20.06.2014 University of Basel, Basel, Switzerland Dehio Christoph;
Stalked alpha-Proteobacteria and relatives: From genes to structure Talk given at a conference FIC domains in Bartonella: Evolution of diverse host effectors from a widely-spread bacteria toxin-antitoxin system 30.03.2014 Marburg, Germany Dehio Christoph;
SPP 1580 International Conference on Intracellular Niches of Pathogens Talk given at a conference Role of type IV secretion systems and their translocated effectors in the intracellular lifestyle of Bartonella spp. 01.10.2013 Glashütten, Germany Dehio Christoph;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Neu aufkommende Infektionskrankheiten – Mensch und Mikrobe, University of Basel, Basel, Switzerland German-speaking Switzerland 2015
Talks/events/exhibitions Ausstellung Robert Koch Stiftung: MenschMikrobe German-speaking Switzerland 2014
Media relations: radio, television Echo der Zeit: Von Zellen, Eiweissen und Genen - Echo aus dem Hörsaal SRF1 German-speaking Switzerland 2013

Awards

Title Year
Elected member of the European Molecular Biology Organisation (EMBO) 2013

Associated projects

Number Title Start Funding scheme
132979 Bacterial Type IV Secretion: Cellular, Molecular, and Evolutionary Basis of the Subversion of Host Cell Functions by Translocated Effector Proteins 01.10.2010 Project funding (Div. I-III)
173119 Bacterial Type IV Secretion (T4S): Cellular, Molecular, and Evolutionary Basis of the Subversion of Host Cell Functions by Translocated Effector Proteins 01.04.2017 Project funding (Div. I-III)

Abstract

In the initial funding period of the SNSF grant 31003A-132979 we used Bartonella and Brucella - two related zoonotic pathogens engaging the widespread type IV secretion (T4S) mechanism for establishing chronic bacterial infection - as models to study the cellular, molecular and evolutionary basis of the subversion of host cell functions by T4S-translocated effector proteins. For the three year prolongation period the established multidisciplinary experimental approach will be extended by adopting yeast as surrogate model for studying conserved eukaryotic processes targeted by T4S effectors. Subproject A will focus on the structure/function analysis of Bartonella effector proteins (Beps) translocated by the VirB T4S system of Bartonella and their physiological consequences on the host, with particular emphasis on studying the subversion of immune signaling processes. Subproject B will focus on the functional analysis of effector proteins translocated by the distinct VirB T4S system of Brucella and their physiological consequences on host cell interaction, with particular emphasis on studying the intracellular trafficking events from a late endosomal compartment, where the VirB system is activated in response to acidification, to the endoplasmic reticulum (ER)-related replicative niche of Brucella. Together, these studies will contribute to establishing a molecular paradigm for the role of T4S effectors in triggering chronic bacterial infection.
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