Overview
Our research project aims to tackle the problem of persistence and chronic infection by Pseudomonas aeruginosa. P. aeruginosa is a gram-negative bacterium found in various environments including soil, water and vegetation. Importantly it is an opportunistic human pathogen, responsible for numerous nosocomial infections in immuno-compromised patients. These infections are fatal in cystic fibrosis patients.
Our project follows several research lines, which deal with essential molecular mechanisms involved in biofilm formation and type VI protein secretion. These two key processes are co-regulated and highly relevant for P. aeruginosa pathogenesis. The regulatory control involves signalling pathways associated with two-component regulatory systems and the intracellular second messenger c-di-GMP. We address these questions using multi-disciplinary approaches in molecular microbiology, genetics, cellular microbiology, structural biology and biochemistry.
(i) P. aeruginosa, such as most microbes exist as surface associated communities called « biofilms ». The biofilm lifestyle is an efficient means for microorganisms to maintain a protected niche. In humans, establishment of the biofilm leads to chronic bacterial infection. Biofilms have been shown to display increased resistance to antibiotic treatment and are recalcitrant to eradication via the immune system. To spawn novel communities in new locations, microorganisms must successfully transit from the biofilm to the planktonic growth state. Whereas molecular knowledge on the biofilm formation process is now increasingly available, how bacterial cells detach is largely unknown. However, a productive field of investigation is likely to be the identification of molecular targets, which induce natural dispersion of the biofilm and make the released planktonic bacteria accessible to efficient therapeutic treatments. Our group will focus on studying key regulators that are involved in the perception of environmental cues that induce biofilm formation or dispersion and on the characterization of the molecular determinants that mechanically contribute to biofilm development and subsequent disruption. In particular we study the Gac/Rsm pathway and how it is influenced by upstream sensors such as RetS and LadS. This central pathway is partly connected with c-di-GMP signalling and we study the molecualr links existing between these two and how it influences the switch between a motile and a sessile lifestyle.
(ii) P. aeruginosa is capable of releasing a wide variety of extracellular hydrolytic enzymes and to inject effectors within host cells for hijacking their signalling pathways. In all cases the secretion mechanism involves multi-protein complexes that are partly embedded within the bacterial cell envelope. Several of these systems have now been well characterized. The secretion of proteins is crucial for many aspects of bacterial pathogenesis since it mediates interaction with the host and contributes to colonization, survival and cytotoxicity. The type VI secretion system (T6SS), which we study in the laboratory, is found in several copies on the P. aeruginosa genome, and is widely distributed among bacterial pathogens. The functionaly and role of the T6SS in P. aeruginosa pathogenesis is many-fold and range from manipulation of eukaryotic host cell to killing of bacterial competitors. Our group is involved in the structural characterization of the supramolecular assembly constituting this nanomachine and in the identification of novel T6SS effectors. This is including discovery of novel bacterial toxins, which is highly relevant for the development of new antimicrobial strategies.
Collaborators
Dr Despoina Mavridou, University Texas Austin
Pr Erh-Min Lai, Academia Sinica Taiwan
Dr John Whitney, McMaster University
Gert Bange and Wieland Steinchen, Max Planck Institute Marburg
Professor Burkhard Tuemmler, Hannover Medical School, Pseudomonas pathogenesis
Dr Rome Voulhoux, Université de la Méditerranée, Type II secretion system
Professor Paul Freemont, Imperial College London, Type VI secretion system
Professor Stephen Matthews, Imperial College London, Fimbrial assembly by the chaperone usher pathway
Professor Gabriel Waksman, Birkbeck College, UCL, Frimbrial assembly by the chaperone usher pathway
Dr Gerald Larrouy-Maumus, Imperial College London, Anibiotic Resistance Diagnostic
Professor Stephen Lory, Harvard Medical School, Regulatory network and signalling
Professor Paul Williams, University of Nottingham, Regulatory network and signalling
Guest Lectures
Gordon Research Conference on Microbial adhesion and Signal transduction. "The Type VI Secretion System (T6SS): A Bacterial Killing Machine"., Gordon Research Conference, Newport, RI, USA, 2019
ETOX 19, European Workshop on Bacterial Protein Toxins The Type VI Secretion System: A bacterial Killing Machine, Davos, Switzerland, 2019
Bacterial Protein Export 2018, The Type VI secretion system: an anti-bacterial nanoweapon,, Leuven, Belgium, 2018
Young Microbiologist Symposium YMS 2018. Pseudomonas aeruginosa lifestyles, bacterial warfare & novel antimicrobials. The Arthur Mitchell Brown Memorial Keynote Lecture, Belfast, UK., 2018
Gordon Research Conference on Protein Transport across Cell Membranes, . Pore-Forming Activity of the Pseudomonas aeruginosa Type III Secretion System Translocon Alters the Host Epigenome, Gordon Research Conference, Galveston, TX, USA, 2018
FEMS 2017. The T6SS: a bacterial killing machine., FEMS, Valencia, Spain., 2017
ASM Microbe 2016. Type VI Secretion System and Bacterial Toxins: A Matter of Friends or Foes., ASM, Boston, USA, 2016
ASM Pseudomonas Conference. The Pseudomonas aeruginosa Type VI secretion system: a weapon for bacterial warfare., ASM, Washington DC, 2015
ASM Conference on Mechanisms of Interbacterial Cooperation and Competition - The P. aeruginosa Type VI Secretion System., Washington, D.C., 2015
Gordon Research Conference on Bacterial Cell Surface -The Pseudomonas aeruginosa Type VI Secretion System., Mount Snow Resort, VT USA,, 2014
The type VI secretion system: On the bacteriophage trail, Université Paris-Descartes, Paris, France, 2012
Key regulatory networks that control biofilm formation and chronic infections in Pseudomonas aeruginosa, ASM Biofilm Conference, Miami, USA, 2012
Regulatory mechanisms switching the Pseudomonas aeruginosa lifestyle towards the biofilm mode, University of Southampton, Southampton, UK, 2012
A regulatory switch controlling Type III and Type VI secretion systems in Pseudomonas aeruginosa., XIIIth International Pseudomonas conference, Sydney, Australia, 2012
Regulatory networks involved in the switch between T3SS and T6SS in P. aeruginosa, Gordon Research Conference on Microbial adhesion and cell signalling, Newport, USA, 2012
Biofilm-specific genes in relation to chronic infections, Eurobiofilm Conference, Copenhagen, Denmark, 2012
Pseudomonas aeruginosa pathogenesis: molecular switches drive the transition towards the biofilm mode, University of Munster, Munster, Germany, 2012
Protein Secretion Systems. What else ?, University Basel, Biozentrum, Basel, Switzerland, 2012
The Type VI Secretion System in Pseudomonas aeruginosa: on the bacteriophage trail., Université Strasbourg, Strasbourg, France, 2012
The Type VI Secretion System in Pseudomonas aeruginosa, Rocky Mountain Laboratories, Hamilton, USA, 2012
The Type VI Secretion System in Pseudomonas aeruginosa, Basel University, Biozentrum, Basel, Switzerland, 2012
The Type VI Secretion System in Pseudomonas aeruginosa, Dundee University, Dundee, UK, 2012
Regulatory switches controlling Pseudomonas aeruginosa lifestyle, Queen Mary University, London, UK, 2012
The type VI secretion system: On the bacteriophage trail, Université Paris-Descartes, Paris, France, 2011
Regulatory mechanisms switching Pseudomonas aeruginosa lifestyles: chronic versus acute infections, Institut Pasteur, Paris, France, 2011
Regulatory switches controlling Pseudomonas aeruginosa lifestyle, Strathclyde University, Glasgow, UK, 2011
Regulatory switches controlling Pseudomonas aeruginosa lifestyle, Washington University, Seattle, USApr, 2011
Regulatory networks involved in the switch between T3SS and T6SS in P. aeruginosa, Imperial College London, London, UK, 2011
Pseudomonas aeruginosa pathogenesis: molecular switches drive the transition towards the biofilm mode, UNIA, Workshop on Pseudomonas aeruginosa: opportunistic pathogen and human infections, Baeza, Spain, 2010
The type VI secretion system: a tubular story, Université Paris-Descartes, Paris, France, 2010
Pseudomonas aeruginosa pathogenesis: molecular switches drive the transition towards the biofilm mode, CIIL, Lille, France, 2010
Pseudomonas aeruginosa pathogenesis: molecular switches drive the transition towards the biofilm mode, Birmingham University, Birmingham, UK, 2010
Pseudomonas aeruginosa lifestyles: molecular switches drive the transition towards the biofilm mode, Technische Universität München, Munchen, Germany, 2010
Pseudomonas aeruginosa pathogenesis: molecular switches drive the transition towards the biofilm mode, SFM 8th General Meeting, Marseille, France, 2010
The bacterial type VI secretion system: on the bacteriophage trail, ASM 110th General Meeting, San Diego, USA, 2010
Pseudomonas aeruginosa lifestyles: molecular switches drive the transition towards the biofilm mode, University Basel, Biozentrum, Basel, Switzerland, 2010
Pseudomonas aeruginosa lifestyles: molecular switches drive the transition towards the biofilm mode, University of Reading, Reading, UK, 2010
Pseudomonas aeruginosa lifestyles: molecular switches drive the transition towards the biofilm mode, Sanger Institute, Cambridge, UK, 2009
The type VI secretion system: a tubular story, Université Paris-Descartes, Paris, France, 2009
Molecular mechanisms of Pseudomonas aeruginosa infections : a matter of lifestyle, ENS, FINOVI, Lyon, France, 2009
The bacterial type VI secretion system: on the bacteriophage trail, Umea University, Umea, Sweden, 2009
Phosphorelay controls biofilm formation and small regulatory RNA expression in Pseudomonas aeruginosa, Nottingham University, Nottingham, UK, 2009
The bacterial Type VI secretion system: yet another player for protein transport across membranes, University of Cambridge, Cambridge, UK, 2009
The bacterial type VI secretion system : yet another player for protein transport across membranes, ESBS Strasbourg, Strasbourg, Fance, 2008
The 'P-usher', a novel bacterial transporter involved in fimbrial assembly and TpsA secretion, Birkbeck College, London, UK, 2008
The 'P-usher', a novel bacterial transporter involved in fimbrial assembly and TpsA secretion, Gordon Research Conference. Bacterial Cell Surfaces, New London, USA, 2008
Two component systems involved ion the control of biofilm formation and virulence in Pseudomonas aeruginosa, Max von Pettenkofer Institut, Munchen, Germany, 2008
The virulence of Pseudomonas aeruginosa, University of Basel, Biozentrum, Basel, Switzerland, 2008
Involvement of Two-component signal transduction systems in biofilm and virulence in Pseudomonas aeruginosa, Centro Nacional de Biotecnología, CSIC, Madrid, Spain, 2008
Research Staff
Research Student Supervision
Howard,S, The P. aeruginosa T6SS - Hcp-dependent secretion
Jones,C, Type VI secretion in Pseudomonas aeruginosa
Moscoso,J, c-di-GMP signalling in Pseudomonas aeruginosa
Muhl,D, Chaperone usher pathway in Pseudomonas aeruginosa
Pissaridou,P, The P. aeruginosa T6SS - The VgrG1b island
Wettstadt,S, The P. aeruginosa T6SS - The VgrG shuttle