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Virulence and communication of Legionella: Molecular determinants of pathogen-host cell interactions

English title Virulence and communication of Legionella: Molecular determinants of pathogen-host cell interactions
Applicant Hilbi Hubert
Number 175557
Funding scheme Project funding (Div. I-III)
Research institution Institut für Medizinische Mikrobiologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Experimental Microbiology
Start/End 01.04.2018 - 31.03.2022
Approved amount 995'018.00
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All Disciplines (2)

Discipline
Experimental Microbiology
Medical Microbiology

Keywords (10)

Type IV secretion; Cellular microbiology; Macrophage; Bacterial virulence; Vesicle trafficking; GTPase; Phosphoinositide lipid; Amoeba; Bacterial effector protein; Dictyostelium

Lay Summary (German)

Lead
Legionellen (Legionella pneumophila) sind Umweltbakterien, welche eine schwere Lungenentzündung namens Legionärskrankheit auslösen können. Die Bakterien vermehren sich in der Umwelt in freilebenden Amöben und nach dem Einatmen in speziellen Immunzellen in der Lunge. Unsere Forschung trägt zum Verständnis der Legionelleninfektion und zu möglichen neuen Therapieansätzen bei.
Lay summary

Legionellen (Legionella pneumophila) vermehren sich in der Umwelt in Amöben und besiedeln Biofilme. Durch Inhalation von feinen Wassertröpfchen (Aerosolen) aus kontaminierten Wassersystemen, z.B. Kühltürmen oder Duschen, gelangen die Legionellen in die menschliche Lunge. Hier vermehren sich die Bakterien in speziellen Immunzellen (Makrophagen) und lösen eine schwere Lungenentzündung, die Legionärskrankheit, aus. Die Krankheit trifft bevorzugt immungeschwächte und ältere Personen und verläuft in ca. 10% der Fälle tödlich.

Legionellen vermehren sich in Wirtszellen in einem speziellen Kompartiment, einer Vakuole. Um dieses Kompartiment zu bilden, verwenden die Bakterien ein Proteintransportsystem, welches über 300 verschiedene sogenannte Effektorproteine in Wirtszellen schleust. In der Wirtszelle beeinflussen diese Proteine zellbiologische und biochemische Prozesse zugunsten der Bakterien. Im vorliegenden Projekt untersuchen wir auf molekularer und zellulärer Ebene den Mechanismus ausgewählter Effektorproteine sowie die bakterielle Kommunikation mittels Signalmolekülen. Dabei kommen sowohl biochemische als auch molekular- und zellbiologische Methoden zum Einsatz. Die erarbeiteten Erkenntnisse liefern grundlegende Einsichten über die Virulenz von Legionellen und finden möglicherweise therapeutische Anwendungen in der Klinik. Unsere Arbeiten im Bereich der Zell-Zell-Kommunikation und Biofilm-Bildung von Legionellen tragen dazu bei, das Auftreten der Bakterien in Wassersystemen zu kontrollieren.

Direct link to Lay Summary Last update: 01.02.2018

Responsible applicant and co-applicants

Employees

Publications

Publication
Migration of Acanthamoeba through Legionella biofilms is regulated by the bacterial Lqs‐LvbR network, effector proteins and the flagellum
Hochstrasser Ramon, Michaelis Sarah, Brülisauer Sabrina, Sura Thomas, Fan Mingzhen, Maaß Sandra, Becher Dörte, Hilbi Hubert (2022), Migration of Acanthamoeba through Legionella biofilms is regulated by the bacterial Lqs‐LvbR network, effector proteins and the flagellum, in Environmental Microbiology, 1.
Bacterial quorum sensing and phenotypic heterogeneity: how the collective shapes the individual
Striednig Bianca, Hilbi Hubert (2022), Bacterial quorum sensing and phenotypic heterogeneity: how the collective shapes the individual, in Trends in Microbiology, 30(4), 379-389.
The Legionella Lqs-LvbR Regulatory Network Controls Temperature-Dependent Growth Onset and Bacterial Cell Density
Hochstrasser Ramon, Hilbi Hubert (2022), The Legionella Lqs-LvbR Regulatory Network Controls Temperature-Dependent Growth Onset and Bacterial Cell Density, in Applied and Environmental Microbiology, 88(5), e02370-21.
Microbe Profile: Legionella pneumophila - a copycat eukaryote
Hilbi Hubert, Buchrieser Carmen (2022), Microbe Profile: Legionella pneumophila - a copycat eukaryote, in Microbiology, 168(3), 1.
The Polar Legionella Icm/Dot T4SS Establishes Distinct Contact Sites with the Pathogen Vacuole Membrane
Böck Désirée, Hüsler Dario, Steiner Bernhard, Medeiros João M., Welin Amanda, Radomska Katarzyna A., Hardt Wolf-Dietrich, Pilhofer Martin, Hilbi Hubert (2021), The Polar Legionella Icm/Dot T4SS Establishes Distinct Contact Sites with the Pathogen Vacuole Membrane, in mBio, 12(5), e02180-21.
Dictyostelium Dynamin Superfamily GTPases Implicated in Vesicle Trafficking and Host-Pathogen Interactions
Katic Ana, Hüsler Dario, Letourneur François, Hilbi Hubert (2021), Dictyostelium Dynamin Superfamily GTPases Implicated in Vesicle Trafficking and Host-Pathogen Interactions, in Frontiers in Cell and Developmental Biology, 9, 731964.
Quorum sensing governs a transmissive Legionella subpopulation at the pathogen vacuole periphery
Striednig Bianca, Lanner Ulrike, Niggli Selina, Katic Ana, Vormittag Simone, Brülisauer Sabrina, Hochstrasser Ramon, Kaech Andres, Welin Amanda, Flieger Antje, Ziegler Urs, Schmidt Alexander, Hilbi Hubert, Personnic Nicolas (2021), Quorum sensing governs a transmissive Legionella subpopulation at the pathogen vacuole periphery, in EMBO reports, 22(9), e52972.
Dictyostelium lacking the single atlastin homolog Sey1 shows aberrant ER architecture, proteolytic processes and expansion of the Legionella-containing vacuole.
HüslerDario, HilbiHubert, LetourneurFrançois (2021), Dictyostelium lacking the single atlastin homolog Sey1 shows aberrant ER architecture, proteolytic processes and expansion of the Legionella-containing vacuole., in Cellular Microbiology, e13318.
Zn2+ Intoxication of Mycobacterium marinum during Dictyostelium discoideum Infection Is Counteracted by Induction of the Pathogen Zn2+ Exporter CtpC.
HannaNabil, BarischCaroline (2021), Zn2+ Intoxication of Mycobacterium marinum during Dictyostelium discoideum Infection Is Counteracted by Induction of the Pathogen Zn2+ Exporter CtpC., in mBio, e01313-20.
Evolution and function of bacterial RCC1 repeat effectors
Swart Anna Leoni, Gomez‐Valero Laura, Buchrieser Carmen, Hilbi Hubert (2020), Evolution and function of bacterial RCC1 repeat effectors, in Cellular Microbiology, 22(10), e13246.
Divergent Evolution of Legionella RCC1 Repeat Effectors Defines the Range of Ran GTPase Cycle Targets.
AL Swart, B Steiner, L Gomez-Valero, S Schütz, M Hannemann, P Janning, M Irminger, E Rothmeier, C Buchrieser, A Itzen, VG Panse, H Hilbi (2020), Divergent Evolution of Legionella RCC1 Repeat Effectors Defines the Range of Ran GTPase Cycle Targets., in mBio, e00405.
Identification of Anti-Mycobacterium and Anti-Legionella Compounds With Potential Distinctive Structural Scaffolds From an HD-PBL Using Phenotypic Screens in Amoebae Host Models.
N Hanna, S Kicka, G Chiriano, C Harrison, HO Sakouhi, V Trofimov, A Kranjc, J Nitschke, M Pagni, P Cosson, H Hilbi, L Scapozza, T Soldati (2020), Identification of Anti-Mycobacterium and Anti-Legionella Compounds With Potential Distinctive Structural Scaffolds From an HD-PBL Using Phenotypic Screens in Amoebae Host Models., in Frontiers in microbiology, 266.
Legionella pneumophila
Swart A. Leoni, Hilbi Hubert (2020), Legionella pneumophila, in Reference Module in Biomedical Sciences, 1.
Legionella quorum sensing meets cyclic-di-GMP signaling.
R Hochstrasser, H Hilbi (2020), Legionella quorum sensing meets cyclic-di-GMP signaling., in Current opinion in microbiology, 9.
Mycobacterium marinum produces distinct mycobactin and carboxymycobactin siderophores to promote growth in broth and phagocytes.
P Knobloch, H Koliwer-Brandl, FM Arnold, N Hanna, I Gonda, S Adenau, N Personnic, C Barisch, MA Seeger, T Soldati, H Hilbi (2020), Mycobacterium marinum produces distinct mycobactin and carboxymycobactin siderophores to promote growth in broth and phagocytes., in Cellular microbiology, e13163.
Phosphoinositides and the Fate of Legionella in Phagocytes.
AL Swart, H Hilbi (2020), Phosphoinositides and the Fate of Legionella in Phagocytes., in Frontiers in immunology, 25.
Quorum sensing controls persistence, resuscitation, and virulence of Legionella subpopulations in biofilms.
PersonnicNicolas, StriednigBianca, HilbiHubert (2020), Quorum sensing controls persistence, resuscitation, and virulence of Legionella subpopulations in biofilms., in ISME Journal, 196.
The structure of the Legionella response regulator LqsR reveals amino acids critical for phosphorylation and dimerization.
R Hochstrasser, CAJ Hutter, FM Arnold, K Bärlocher, MA Seeger, H Hilbi (2020), The structure of the Legionella response regulator LqsR reveals amino acids critical for phosphorylation and dimerization., in Molecular microbiology, 1070.
Transcriptional Responses of Dictyostelium discoideum Exposed to Different Classes of Bacteria.
O Lamrabet, A Melotti, F Burdet, N Hanna, J Perrin, J Nitschke, M Pagni, H Hilbi, T Soldati, P Cosson (2020), Transcriptional Responses of Dictyostelium discoideum Exposed to Different Classes of Bacteria., in Frontiers in microbiology, 410.
Distinct Mycobacterium marinum phosphatases determine pathogen vacuole phosphoinositide pattern, phagosome maturation, and escape to the cytosol.
H Koliwer-Brandl, P Knobloch, C Barisch, A Welin, N Hanna, T Soldati, H Hilbi (2019), Distinct Mycobacterium marinum phosphatases determine pathogen vacuole phosphoinositide pattern, phagosome maturation, and escape to the cytosol., in Cellular microbiology, e13008.
Migration of Acanthamoeba castellanii Through Legionella Biofilms.
R Hochstrasser, H Hilbi (2019), Migration of Acanthamoeba castellanii Through Legionella Biofilms., in Methods in molecular biology (Clifton, N.J.), 79.
Perturbation of Legionella Cell Infection by RNA Interference.
B Steiner, AL Swart, H Hilbi (2019), Perturbation of Legionella Cell Infection by RNA Interference., in Methods in molecular biology (Clifton, N.J.), 191.
PIKfyve/Fab1 is required for efficient V-ATPase and hydrolase delivery to phagosomes, phagosomal killing, and restriction of Legionella infection.
CM Buckley, VL Heath, A Guého, C Bosmani, P Knobloch, P Sikakana, N Personnic, N Personnic, SK Dove, RH Michell, R Meier, H Hilbi, T Soldati, RH Insall, JS King (2019), PIKfyve/Fab1 is required for efficient V-ATPase and hydrolase delivery to phagosomes, phagosomal killing, and restriction of Legionella infection., in PLoS pathogens, e1007551.
Quantitative Imaging Flow Cytometry of Legionella-Containing Vacuoles in Dually Fluorescence-Labeled Dictyostelium.
A Welin, S Weber, H Hilbi (2019), Quantitative Imaging Flow Cytometry of Legionella-Containing Vacuoles in Dually Fluorescence-Labeled Dictyostelium., in Methods in molecular biology (Clifton, N.J.), 161.
Quorum sensing modulates the formation of virulent Legionella persisters within infected cells.
N Personnic, B Striednig, E Lezan, C Manske, A Welin, A Schmidt, H Hilbi (2019), Quorum sensing modulates the formation of virulent Legionella persisters within infected cells., in Nature communications, 5216.
Role of the small GTPase Rap1 in signal transduction, cell dynamics and bacterial infection
Hilbi Hubert, Kortholt Arjan (2019), Role of the small GTPase Rap1 in signal transduction, cell dynamics and bacterial infection, in Small GTPases, 10(5), 336-342.
Single Cell Analysis of Legionella and Legionella-Infected Acanthamoeba by Agarose Embedment.
N Personnic, B Striednig, H Hilbi (2019), Single Cell Analysis of Legionella and Legionella-Infected Acanthamoeba by Agarose Embedment., in Methods in molecular biology (Clifton, N.J.), 191.
The pleiotropic Legionella transcription factor LvbR links the Lqs and c-di-GMP regulatory networks to control biofilm architecture and virulence.
R Hochstrasser, A Kessler, T Sahr, S Simon, U Schell, L Gomez-Valero, C Buchrieser, H Hilbi (2019), The pleiotropic Legionella transcription factor LvbR links the Lqs and c-di-GMP regulatory networks to control biofilm architecture and virulence., in Environmental microbiology, 1035.
The large GTPase atlastin controls ER remodeling around a pathogen vacuole
Steiner Bernhard, Weber Stephen, Kaech Andres, Ziegler Urs, Hilbi Hubert (2018), The large GTPase atlastin controls ER remodeling around a pathogen vacuole, in Communicative & Integrative Biology, 11(2), 1-5.
Acanthamoeba and Dictyostelium as Cellular Models for Legionella Infection
Swart A. Leoni, Harrison Christopher F., Eichinger Ludwig, Steinert Michael, Hilbi Hubert (2018), Acanthamoeba and Dictyostelium as Cellular Models for Legionella Infection, in Frontiers in Cellular and Infection Microbiology, 8, 61.
Legionella quorum sensing and its role in pathogen–host interactions
Personnic Nicolas, Striednig Bianca, Hilbi Hubert (2018), Legionella quorum sensing and its role in pathogen–host interactions, in Current Opinion in Microbiology, 41, 29-35.
A uniform cloning platform for mycobacterial genetics and protein production
Arnold F.M., Hohl M., Remm S., Koliwer-Brandl H., Adenau S., Chusri S., Sander P., Hilbi H., Seeger M.A. (2018), A uniform cloning platform for mycobacterial genetics and protein production, in Scientific Reports, 8(1), 9539.
Formation of the Legionella-containing vacuole: phosphoinositide conversion, GTPase modulation and ER dynamics
Steiner Bernhard, Weber Stephen, Hilbi Hubert (2018), Formation of the Legionella-containing vacuole: phosphoinositide conversion, GTPase modulation and ER dynamics, in International Journal of Medical Microbiology, 308(1), 49-57.
Legionella-Containing Vacuoles Capture PtdIns(4)P-Rich Vesicles Derived from the Golgi Apparatus.
S Weber, B Steiner, A Welin, H Hilbi (2018), Legionella-Containing Vacuoles Capture PtdIns(4)P-Rich Vesicles Derived from the Golgi Apparatus., in mBio, e02420.

Awards

Title Year
Membership Faculty Opinions (formerly F1000Prime) 2020
Fellowship American Academy of Microbiology 2018

Associated projects

Number Title Start Funding scheme
184024 Antibacterial function of mammalian lipid droplets; high-resolution characterization of LD-pathogen contact sites 01.09.2019 Early Postdoc.Mobility
200706 Pathogen-phagocyte small molecule inter-kingdom signaling 01.04.2021 Project funding (Div. I-III)
125369 Legionella trafficking and host phosphoinositide metabolism 01.05.2009 Project funding (Div. I-III)
153200 Formation of the Legionella-containing vacuole: Effectors targeting retrograde trafficking and microtubules 01.01.2015 Project funding (Div. I-III)
170811 Enhanced Resolution Confocal Laser Scanning Microscope 01.10.2017 R'EQUIP
153200 Formation of the Legionella-containing vacuole: Effectors targeting retrograde trafficking and microtubules 01.01.2015 Project funding (Div. I-III)

Abstract

Environmental bacteria of the genus Legionella grow within free-living amoeba and, upon inhalation of contaminated aerosols, within lung macrophages, thereby causing a severe pneumonia termed “Legionnaires’ disease”. Employing an evolutionarily conserved mechanism, Legionella pneumophila replicates in protozoan and mammalian host cells in a unique compartment, the “Legionella-containing vacuole” (LCV). LCVs avoid fusion with bactericidal lysosomes, but extensively communicate with the endosomal, secretory and retrograde vesicle trafficking pathways, and intimately associate with the endoplasmic reticulum (ER).LCV formation is a complex and robust process that requires the bacterial Icm/Dot type IV secretion system (T4SS). This T4SS translocates the astonishing number of 300 different so-called “effector proteins" into eukaryotic host cells, where they subvert pivotal processes such as signal transduction and vesicle trafficking. Some of these effectors target host components implicated in antibacterial defence or membrane dynamics, such as the chelator phytate, small GTPases, phosphoinositide (PI) lipids, the retromer complex, or the microtubule cytoskeleton. Moreover, the Legionella quorum sensing (Lqs) system and the small molecule Legionella autoinducer-1 (LAI-1) not only mediate bacterial quorum sensing and intra-species signaling, but also modulate host cell migration and thus promote inter-kingdom signaling.Research in our lab addresses the molecular mechanisms of LCV formation and cell-cell communication of Legionella species. Here, we focus on the molecular mechanism of L. pneumophila effectors targeting the retromer coat complex or distinct small and large GTPases. Our studies will shed light on the mode of action of novel translocated bacterial virulence factors and yield fundamental new insights into the cellular processes underlying the regulation of retrograde trafficking, vesicle fusion and fission, as well as the modulation of small and large GTPases.
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