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Dernière mise à jour : Mai 2018

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Pole « Bacterial Adaptation and Pathogenesis »

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RESEARCH SUMMARY

As bacterial model, the PIMs team is expert in the study of the virulence of Bacillus cereus (Bc) and its mechanisms of resistance to the host immune system (38 publications, 1 patent). Bc is the second agent causing collective food poisoning and is also responsible for severe clinical infections such as sepsis and meningitis. Bc is able to destroy the intestinal barrier and enter the bloodstream. Thus, after ingestion or during infection by injury, the bacterium enters in contact with immune cells. The bacterium then resists the bactericidal properties of macrophages, in particular by surviving the nitrogen response. But this induced host immune response may be deleterious for the surrounding microbiota and contributes to the pathogenesis and spread of Bc. 
The goal of the team is to analyze the impact of the host immune response on the virulence of pathogenic bacteria in their biotic environment, taking into account the microbiota of the host. The innate immune response is characterized by the production of toxic substances such as oxygen and nitrogen derivatives. These compounds have a toxic effect against pathogens but also against the host and potentially also against its microbiota. However, there is little data on the impact of this response on the pathophysiology of pathogen / microbiota / host interactions. The objective of the team is therefore to study on one hand the effects of the immune response on pathogenic bacteria, and on the other hand to characterize the impact of the microbiota on the modulation of the host response and the development of pathogen infectivity. 
Based on our previous data, the projects of the team are divided into four axes:

1-Understand the mechanisms of bacterial resistance to the host immune system

2-Propose diagnostic tools

3-Develop alternative antibiotic strategy

4-Study pathogen / host / microbiota interactions

5-Increase public communication

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Theme 1.- Interaction between B. cereus and host cells

Our aim is to identify bacterial factors involved in the passage through the intestinal epithelium of the host and characterize the strategies developed by bacteria belonging to the group B. cereus, to resist and adapt to the innate immune response during the early stages of infection.

Different aspects involved in the infectivity of B. cereus are examined:
i) Adhesion and cytotoxicity to eukaryotic epithelial cells.
ii) Interaction with phagocytic macrophage-like cells.
iii) Survival in macrophages.
iv) Resistance to the oxidative and nitrogen response.

Fundings: 

-European Joint Project (EJP) One health. projet TOX-detect 2018-2020: Development and harmonisation of innovative methods for comprehensive analysis of foodborne toxigenic bacteria, ie. Staphylococci, Bacillus cereus and Clostridium perfringens. 2 M€

-MEM-INRA MicrobNO Impact of the host nitrogen response following bacterial infection on the microbiota 2017-2018. 50 k€

  

Macrophage

Adhesion of B. cereus to an HeLa cell.

Theme 2.- Diagnostic

PIMs’s diagnostic activity is focused on development of bioelectrochemical, PCR-based and paper-based  biosensors for applications in food and water security.  We develop sensing elements (DNA probes, aptamers, antibodies) that recognize bacterial biomarkers and innovative immobilization strategies for biomolecules, including chemical grafting, affinity interactions or formation of host-guest interactions.

Beside the elaboration of novel biosensors for bacterial detection, the PIMs team is highly experienced in discovery of new biomarkers of bacterial pathogenicity. PIMs present research interests include detections of B. cereus spp. in clinical and environmental samples and Campylobacter spp. in poultry meats. 

Fundings:  

-Initiative d'excellence Paris Saclay. Idex. Projet Idex Bc 2017-2019: Biomarqueurs des Bacillus cereus pathogènes, 45 k€

-INRA-prematuration 2017-2018: Biomarqueurs des Bacillus cereus pathogènes, 35 k€

-Initiative d'excellence Paris Saclay. AAP Prématuration Idex. Projet BBC2 2018-2019: Développement d’un kit de détection de biomarqueurs des Bacillus cereus pathogènes, 65 k€

Theme 3.- Therapeutic innovation

Antibiotics have drastically reduced the mortality associated with infectious diseases. However, their overuse prompted bacteria to develop resistance. Since 40 years, the rate of discovery of new antibiotics has constantly decreased and no “first in class” antibiotic has been proposed. Meanwhile, drug-resistant bacteria have spread, leading to 23000 deaths/year in the EU.

We identified an innovative therapeutic target for the development of new drugs. This target is a bacteria-specific protein with a key role in resistance to the host immune response. We identified inhibitors of this target able to specifically block bacterial survival during immune stress in vivo. These promising drug candidates are currently tested for safety to the host and for activity against serious threat pathogens.

Fundings: 

-Initiative d'excellence Paris Saclay. AAP Prématuration Idex. Projet NewMed 2015-2016: Une nouvelle cible pour le développement d'antimicrobiens, 80 k€

-SATT Paris Saclay. projet de maturation 2016-2018. An innovative target for the development of new drugs. 650 k€

-Initiative d'excellence Paris Saclay. AAP Prématuration Idex. Projet NewMed2.0 2018-2019: Un antimicrobien innovant pour booster le système immunitaire, 70 k€

-Toulouse White Biotechnology (TWB) Biosciences and bio production. Projet 2019-2020. PROFILING A MULTI-FUNCTION PROTEIN AS AN INNOVATIVE TARGET FOR THE DEVELOPMENT OF NEW DRUGS.

 

Theme 4.- Host/Pathogen/Microbiota

The innate immune response produces toxic substances to fight pathogens. However, these substances can also be deleterious for the host and its microbiota. Using Omic analysis and appropriate in vivo models, we study the impact of the innate immune response on the virulence of digestive pathogens and on the intestinal microbiota, and in return characterize the impact of the microbiota on the modulation of the host response and on bacterialpathogenicity. The study of this “ménage à trois” -host/pathogen/microbiota- may allow identifying new biomarkers for better diagnosis of infections and inflammatory diseases.

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Fundings:

-MEM-INRA MicrobNO Impact of the host nitrogen response following bacterial infection on the microbiota 2017-2018, 55 k€

-MEM-INRA. 2017-2018. Projet Metafoldscan. Structuring screening of microbial ecosystems, 50 k€

Theme 5.- Communication

Last but not least, we set up a blog (https://bd-bacterie.com) and a multi-media comic to communicate with the general public on the use of antibiotics and on our current research.

Fundings:

-Fondation Carasso, COMPOSER LES SAVOIRS POUR MIEUX COMPRENDRE LES ENJEUX DU MONDE CONTEMPORAIN. Axe Art citoyen. Projet les antibiotiques ont la parole. 2016-2017, 50 k€

-IDEX Paris-Saclay – Science et Société-La Diagonale Paris-Saclay2018: Bande dessinée multimédia, 5 k€

-Ile de France 2018-2019. Projet: La Science pour tous, culture scientifique, technique et industrielle, 20 k€

-IDEX Paris-Saclay – Science et Société-La Diagonale Paris-Saclay 2019-2020: Science et jeux, 5 k€