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Introduction team

Birth of TrEE

Two teams of the TIMC laboratory, respectively the GEM team (Genomics and Microbial Evolution) and the TheREX team (Experimental Recombinant Therapeutics) have merged to give rise to the TrEE team.

The GEM team had been studying the genomic and ecological bases of bacterial evolution for many years while the TheREx team had been interested in the interactions between microorganisms and their host in various  pathological situations. Merging  the two teams did not result in a simple addition of researchers but synergistically bloomed instead into  complementary approaches going from  fundamental studies on  evolutionary and adaptive processes, to  studies of the human microbe interface in health. We place ourselves in the field of microbiology and biotechnologies  for health by proposing a continuum between fundamental and translational research, with the objective of diagnostic and/or therapeutic innovations.
The team is co-directed by Prof. Dominique Schneider and Prof. Bertrand Toussaint.

Scientific theme and general objectives

We are interested in the evolutionary mechanisms involved in the adaptation of microorganisms to their environment, from in vitro culture  to their eukaryotic hosts (including  human hosts).
We tackle a wide range of research axes, such as the link between structure and gene expression, the mechanisms underlying the acquisition of antibiotic resistance, or the functional organisation of complex microbial populations and the microbiota. We address these challenges through interdisciplinary approaches that combine systems biology, synthetic biology, experimental evolution (in vivo, in silico), biochemistry, cell biology, genetics, genomics, metagenomics, phylogenomics, metabolomics, immunology, bioinformatics, biophysics, statistics, and medicine.


This interdisciplinarity allows us to study the dynamics of interactions in a living system at all levels, i.e. interactions within the cells (between mutations, genes, genes & proteins & metabolites, between structure and genome expression), interactions between cells within a population, populations within microbial communities, and interactions between microbial populations and their hosts.

The pairing of fundamental research axes and both technological and translational axes paves the way for innovation in diagnostics and/or new therapies against infectiologious diseases and more widely, in the field of microbiota/hosts interactions.

Research topics

Axis #1: Metabolism evolution and engineering

Coordinators: Dr. Audrey le Gouellec & Dr. Fabien Pierrel

The axis “metabolism evolution and engineering” gathers clinicians and researchers who study the evolution of microbial metabolism and engineer intelligent microbes for health benefits. The capacity of microorganisms to colonize extremely diverse ecological niches results in part from the versatility and the adaptability of their metabolism, which is defined as the set of chemical reactions that are necessary for a species to survive, grow, reproduce, and interact with its environment. In the lab, we study metabolic evolutions at different scales by combining experimental and bioinformatics approaches. We have access to the high resolution mass spectrometry platform « Grenoble Expertise in Metabolomics » (GExiM), which is supervised by scientists from our laboratory, in particular Audrey le Gouellec. Among different projects, we study the evolution of the metabolism of Pseudomonas aeruginosa strains in cystic fibrosis patients over several years, notably with regard to virulence, antibiotic resistance, and pathogenicity. We also look into isoprenoid quinones which play a central role in bacterial energetic metabolism. We study the biochemistry of the quinones biosynthetic pathways, their contribution to bacterial physiology, and their evolution over the last 2 billion years. Building on all this knowledge, we use synthetic biology approaches to engineer live biotherapeutic products that we test on infection models and animal models of inflammatory diseases. The axis “metabolism evolution and engineering” is also enriched by several transversal projects rooted in other axes of TrEE, like the study of adaptive diversification in the LTEE (Long Term Evolution Experiment) and the decomposition of metabolic networks into adaptive units (axis 3), and the adaptive response to antifungal drugs (axis 4).

 

Axis #2: Microbiota evolution and engineering

Coordinators: Prof. Antonia Suau-Pernet & Dr. Dalil Hannani

We study the impact of gut microbiota on the host, in particular on its immune system in health and diseases (response to vaccination, cancer, auto-immunity, acute, and chronic infections). In order to do so, we study the composition of the gut microbiota (16S or metagenomesequencing), its function (metabolomics analyses) as well as the host immune status (gut mucosal and systemic immunity).
We are developing several strategies to manipulate and optimize the host gut microbiota, notably through prebiotics or probiotics administration, or through  bacteria that are engineered on relevant metabolic pathways. These strategies are designed to improve cancer immunosurveillance, the response rate to cancer immunotherapies, or to promote immune tolerance in the context of inflammatory bowel diseases etc....
We analyse the intestinal microbiota of preterm infants to determine the dynamic of species implantation and the genome evolution of strains colonizing the gut to understand how bacteria and their host interact. The microbiota axis is highly translational, from preclinical research to clinical studies aiming at demonstrating the critical role of gut microbiota metabolic functions in the response to immunotherapy in NSCLC (Non-Small Lung Cell Carcinoma).

 

Axis #3: Evolution of the structure and expression of (meta)-genomes

Coordinators: Dr. Ivan Junier & Dr. Thomas Hindré

The axis « Evolution of the structure and expression of (meta)-genomes » aims at investigating the genomic determinants responsible for the remarkable adaptive properties of microorganisms (archaea and bacteria). It gathers researchers in the domain of molecular genetics, experimental evolution, computational biology, bioinformatics and biophysics.
The content and organization of genomes are shaped by natural selection (and to some extent by neutral drift), which operate at multiple time scales, from a few generations to billions generations. As a result, genomes are complex mosaics of stable and dynamical structures that provide microorganisms with extraordinary adaptive capacities. In this axis, we study mechanisms associated with this plasticity in order to predict adaptive responses of microorganisms in the context of Health, as in the case of the emergence of pathogens and antibiotics resistance. To this end, we combine three evolutionary approaches:

  • i) in vitro evolution experiments, with a focus on the long-term experimental evolution (LTEE) of Escherichia coli, to characterize molecular and ecological mechanisms underlying adaptive properties, and to apprehend the impact of point and structural mutation rates on these process;
  • ii) comparative genomics and phylogenomics reconstructions of in natura genomes allowing to exploit both conservation and dynamical properties of genomes over long time scales;
  • iii) in silico experiments allowing to test, at large scales and at long term, the impact of different parameters on evolutionary trajectories. We also develop biophysical models and statistical tools dedicated to the study of chromosomes in order to understand the impact of the tridimensional structuring of genomes on the functioning of microorganism.

 

Axis #4: Microbial evolution toward resistance to antimicrobials

Coordinators: Prof. Muriel Cornet & Dr. Corinne Mercier

The objectives of this research axis cover the analysis of evolutionary trajectories, which lead to the outcome of resistance (intrinsic resistances, resistances to low doses and high doses of antimicrobials) as well as tolerance mechanisms to antibiotics and antifungal agents. This axis includes in vitro (induction of resistances by application of antibiotic or antifungal pressures), in natura (in patients or in environment) as well as in silico studies, which require various technological approaches: microbiology, metagenomics, genetics, cell biology, biochemistry, metabolomics, lipidomics, immunology, epidemiology, multivariate analyses, … The results of fundamental studies are developed into novel diagnosis tests and new approaches to fight the targeted infectious agents (Escherichia coli, Pseudomonas aeruginosa, Streptomyces spp, Candida spp, and zoonotic agents…).

 

Axe #5: Vectorization and membranes

Coordinators: Dr. Béatrice Schaack & Prof. Jean-Luc Lenormand

The "Vectorization and Membranes" axis focus on the study of membranes and membrane proteins in the context of host-pathogen interactions, the determination of membrane antigenic targets and the influence of the lipid environment on the structure and function of membrane proteins. We use several experimental approaches including the production and the characterization at the biochemical and biophysical levels of extracellular vesicles from different prokaryotic and eukaryotic organisms, the production of membrane proteins in the form of proteoliposomes using cell-free expression systems in the presence of synthetic lipids of different compositions, the use of microscopy techniques (AFM, electron, fluorescence), DLS, impedance spectroscopy (Tethapod) and circular dichroism to name a few. In order to allow a better internalization of certain macromolecules, vectorization systems are used such as cell penetrating peptides and synthetic liposomes. These biotechnological approaches allow a better understanding at the level of pathogen and host cell membranes of certain molecular mechanisms responsible for pathogenesis and provide innovative therapeutic or vaccine solutions. These approaches are used to treat bacteria that are multi-resistant to antibiotics, as well as fungal infections and certain types of cancer.

 

Current research programs
 

COVID-19 biomarkers

CoVID-19 biomarkers pilot survey
Supervisor: Audrey Legouellec
Contract: Fondation Université Grenoble Alpes - [2020-2022]

DEEPCROSS

New therapeutic solutions in oncology.
Supervisor: Jean-Luc Lenormand
Contract: SATT Linksium - [2020-2021]

dEEPEN

Molecular and evolutionary principles governing enzyme regioselectivity.
Supervisor : Ivan Junier
Contract : Agence Nationale de la Recherche (ANR-19-CE45-0013) - [2020-2024]
The exploitation of evolutionary information, and more particularly of residue coevolution, has revolutionized protein structure predictions. Adaptation of the methods issued from these analyses to the prediction and design of enzymatic functions remains an open problem. Enzymatic functions are indeed characterized by an internal dynamics of proteins that is difficult to model and study experimentally. In this project, we tackle this problem by studying in detail the capacity of certain hydroxylases of the flavin-containing monooxygenase (FMO) protein family to realize their reaction at different positions of the aromatic cycle of ubiquinone (UQ), a molecule key to the production of cellular energy. More precisely, UQ biosynthesis pathway involves three hydroxylation reactions occurring on three carbons of the UQ aromatic ring.

DIVIN

Dissemination and evolution of Resistance Integrons: effects of biofilm lifestyle and antibiotic stress.
Contract: Agence Nationale de la Recherche - [2020-2024]

EvoloWine

Experimental evolution in extreme environments of the lactic acid bacterium Oenococcus oeni and applications to the selection of more efficient malolactic yeasts.
Contract: Agence Nationale de la Recherche - [2020-2024]

METAQUIN

Metagenomics investigation of quinone production in anoxic sea layers.
Supervisor : Sophie Abby
Contract : IDEX Université Grenoble Alpes - Initiatives de recherche stratégiques (IRS) - [2020-2021]

MIMIC

Multi-scale modeling and data integration for bacterial chromosome engineering.
Supervisor : Ivan Junier
Contract : CNRS 80|Prime (Projet de recherche inter-instituts multi-équipes) - [2020-2023]
The MIMIC project - Multiscale Modeling and Data Integration for Bacterial Chromosome Engineering - aims to develop a modeling and data integration platform to address two crucial issues in systems and synthesis biology: rationalization and engineering of the bacterial chromosome.

MMAVAX

Vaccine against Pseudomonas aeruginosa.
Supervisor: Audrey Legouellec
Contract: SATT Linksium - [2020-2022]

M4Vax

Molecular Mechanisms of gut Microbiota and derived Metabolites governing differential Immune response to TLRL stimulation upon Vaccination.
Supervisor: Dalil Hannani
Contract: IDEX Université Grenoble Alpes - [2019-]

O2-taboo

O2-independent hydroxylation and anaerobic ubiquinone synthesis.
Supervisor: Fabien Pierrel
Contract: Agence Nationale De La Recherche (ANR-19-CE44-0014) - [2019-2023]
By combining complementary approaches, the O2-taboo project addresses first-rate questions in microbial physiology, cell biochemistry and evolutionary biology. Overall, our results will lead to significant advances in elucidating (i) the regulation and physiological importance of a novel conserved pathway in proteobacteria, (ii) the molecular function and supramolecular organization of UbiT,U,V proteins, (iii) a novel chemistry for O2-independent hydroxylation reactions, (iv) the distribution and evolution of UQ biosynthetic pathways in proteobacteria, (v) the role of the UbiT,U,V and UbiT proteins in the regulation and physiological importance of a novel conserved pathway in proteobacteria, and (vi) the role of the UbiT,U,V and UbiT,U,V proteins in the regulation and physiological importance of a novel conserved pathway in proteobacteria.

GeWiEp

Epistatic interactions at the level of the bacterial genome: extent, emergence and molecular basis.
Contract: Agence Nationale de la Recherche (ANR-18-CE35-0005) - [2018-2023]

TULAMIBE

Evaluation of the conditions and mechanisms of prolonged survival of Francisella tularensis in the environment and countermeasures.
Supervisor: Max Maurin
Contract: Agence Nationale De La Recherche (ANR-17-ASTR-0024) - [2017-2020]
The main objective of the TULAMIBE project is to define, in experimental and natural situations, the conditions and mechanisms of prolonged survival of Francisella tularensis in the hydro-telluric environment. This bacterium, which is highly infectious and virulent in humans and many animals, is responsible for tularemia, a zoonosis present in the northern hemisphere. This disease has a major public health and economic impact in highly endemic countries.

ImmunoFiber

Supervisor: Dalil Hannani
Contract: Ligue contre le Cancer - Comité Isère [2018-2021], IDEX IRS Université Grenoble Alpes [2018-2022], GEFLUC [2017-2022]

(An)aeroUbi

Characterization and physiological importance of ubiquinone biosynthesis under different oxygen tensions.
Supervisor: Fabien Pierrel
Contract: Agence Nationale De La Recherche (ANR-15-CE11-0001) - [2015-2021]
To produce their energy in the absence of oxygen (anaerobic), bacteria use anaerobic respiration which requires quinones. In anaerobic conditions, the function of ubiquinone (UQ) is not known. Its biosynthesis pathway is not characterized and involves hydroxylases unknown to date. By studying the bacterium Escherichia coli, we want to elucidate the anaerobic biosynthesis pathway of UQ, characterize the associated proteins and understand the functions of UQ.

LIA PredEvo

International research laboratory 'Predicting evolution'.
Contract: CNRS, Université Grenoble Alpes, Michigan State University - [2015-2023]

 

Recent research programs

Convention Université Antananarivo

Thesis co-founding of Tahinamandrato Rasamoelina.
Supervisor: Muriel CORNET
Contract: Convention Université d'Antananarivo (Madagascar) - Université Grenoble Alpes - [2016-2018]

SENSIFONG

New antifungal sensitivity test.
Contract: SATT Linksium, Technology transfer and startup building Grenoble Alpes - Université Grenoble Alpes - [2016-2018]

TULASEQ

Specific support for defence research and innovation work.
Supervisor: Max MAURIN
Contract: Agence Nationale de la Recherche (ANR-15-ASTR-0021) - Université Grenoble Alpes - [2015-2019]
High throughput sequencing (NGS) for the development of new genotypic markers in Francisella tularensis: implications for the epidemiological surveillance of tularemia in France and in the field of bio-defense.

FungiBET

Study of a new potential anti-fungal therapeutic target.
Supervisor: Muriel CORNET
Contract: Agence Nationale de la Recherche (ANR-14-CE16-0027) - Université Grenoble Alpes - [2014-2018]
Study of a new potential anti-fungal therapeutic target: structure, function and inhibition of fungal BET bromodomains.

FINOVI

Supervisor: Jean-Luc LENORMAND
Contract: Fondation FINOVI - Université Grenoble Alpes - [2015-2017]

CoEvo

Co-evolving units of genomes.
Supervisor: Ivan JUNIER
Contract: Programme ATIP-AVENIR - CNRS - [2014-2019]

 

Team members
Presentation of team members (introductory sentence)

The team is co-directed by Prof. Dominique Schneider and Prof. Bertrand Toussaint.

Team coordinator(s)

Permanent members

Others members

PhD students

Thesis

TrEE phd thesis:

Platforms - Resources
EXPERIMENTAL INFECTIOLOGY PLATFORM

PIE

 

Experimental Infectious Diseases Platform

 

   

enumeration

  
MOLECULAR SCREENING VIDEOMICROSCOPIA

 

PIE1 PIE2

Applications areas :

  • Enumeration

  • Invasion

  • Proliferation

  • Interactions with the host

  • Molecular screening

  • Cellular dynamics

PIE3

Aims : evaluate repression or gene expression
in bacteria depending on their environment

 

Place : Jean Roget building
               (UGA - Site Santé)

 

Scientific supervisor :
  Delphine Aldebert

 

 

 

 

PIE4

Aims : evaluate the action of antifungals on the chitin content of yeasts

 

PIE5

Aims: enumeration of parasitic cysts (Dolichos-FITC) in brain crushes

 

____________________________________________________________________________________________________________

CYTOLOGY HISTOLOGY UNIT

 

University Medical-Technical Unit of Cytology Histology

 

cyto cyto

 

The objective of the unit is to provide expertise in the field of morphological analysis through the examination of histological sections but also immunolabels for the detection of specific antigens.
A quantitative approach can also be taken depending on the type of immunolabelling.

 

* Place : Bâtiment Jean Roget

  • 1st floor, room 113 :  Impregnation and inclusion in paraffin  -  Colorations  -  Immunolabelling
  • 4th floor, room 410 (air-conditioned) : Paraffin cutting – Cryostat cutting

 

* Scientific supervisor : Dr Jean Boutonnat PH DACP

* Technical supervisor : Véronique Curri

 

Teaching-Training

The multidisciplinary nature of the research activities of the TrEE team is based on the association of researchers and teacher-researchers attached to a large panel of french CNU sections (64, 65, 44.01, 82, 87 ...) and CNRS commissions (7, 16, 21, 28, 51, ...). This particularity leads logically to the involvement of the team members in teaching and training activities at all levels (from Bachelor's to Doctorate) and in several components of the Grenoble Alpes University (Medicine, Pharmacy, Chemistry-Biology departments) but also of the CNAM Paris. These include courses in microbiology, prokaryotic genetics, molecular and cell biology, infectious diseases, host-pathogen interactions, parasitology, animal biology, differentiation and development, biochemistry, systems biology of biotechnologies, immunology and immuno-oncology.
In addition, several members of the team have pedagogical and/or collective responsibilities;

 

Contact

Phone: 04 76 63 74 39 -
Address: Site Santé, Bât Jean Roget, Domaine de la Merci, 38000 La Tronche