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Roles of TNF receptors in immunoregulation of responses to mycobacterial infections

English title Roles of TNF receptors in immunoregulation of responses to mycobacterial infections
Applicant Garcia-Gabay Irène
Number 146833
Funding scheme Project funding
Research institution Département de Pathologie et Immunologie Faculté de Médecine / CMU Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Immunology, Immunopathology
Start/End 01.04.2013 - 31.03.2016
Approved amount 343'960.00
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Keywords (1)

TNF, TNFR1, BCG, tuberculosis, anti-TNF therapies

Lay Summary (French)

Lead
Les molécules nécessaires pour la défense immunitaire contre des microorganismes sont impliquées dans le développement des pathologies inflammatoires graves. Le TNF, médiateur principal de l’inflammation, est nécessaire pour l'immunité contre des bactéries intracellulaires telles que Mycobacterium tuberculosis agent causant la tuberculose. Des anti-TNF sont utilisés efficacement pour traiter des maladies chroniques mais une diminution de l’immunité anti-bactérienne est observée chez ces patients
Lay summary
  

Contenu et objectifs du travail de recherche

 Notre principal objectif est de contribuer à la compréhension de mécanismes cellulaires et moléculaires de défense immunitaire contre des mycobactéries et d’élucider le rôle du TNF et ses récepteurs dans la protection contre des mycobactéries ainsi que dans les réactions inflammatoires. Nos travaux précédent on porté sur la caractérisation des cellules produisant le TNF et de leur différentes formes moléculaires et activités biologiques. Nous souhaitons i) identifier des cellules qui répondent au TNF dans différentes situations d’activation soit inflammatoires soit infectieuses et ii) caractériser les récepteurs et les molécules intracellulaires qui déterminent une réponse appropriée ou qui peuvent dysfonctionner et générer une pathologie. Nous cherchons également iii) à améliorer des traitements anti-tuberculeux basés sur des connaissances sur les différents rôles du TNF dans la formation et maintient des granulomes.

 

Contexte scientifique et social du projet de recherche

 

Nos travaux généreront des informations inédites sur des cellules répondant au TNF et sur des mécanismes spécifiques d’inflammation et de réponse immunitaire engendrées. Nos résultats permettront d’envisager de nouvelles cibles thérapeutiques pour enrayer l’inflammation en préservant les réponses immunitaires contre des mycobactéries pathogènes telles que Mycobacterium tuberculosis.

 

Keywords

 

Tuberculose, réponse immunitaire, inflammation, infection, Tumor Necrosis Factor ou TNF, TNF récepteurs, cytokines.

Direct link to Lay Summary Last update: 05.04.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
GM-CSF targeted immunomodulation affects host response to M. tuberculosis infection
Benmerzoug Sulayman, Marinho Fabio Vitarelli, Rose Stéphanie, Mackowiak Claire, Gosset David, Sedda Delphine, Poisson Emeline, Uyttenhove Catherine, Van Snick Jacques, Jacobs Muazzam, Garcia Irene, Ryffel Bernhard, Quesniaux Valerie F. J. (2018), GM-CSF targeted immunomodulation affects host response to M. tuberculosis infection, in Scientific Reports, 8(1), 8652-8652.
Transmembrane TNF and Partially TNFR1 Regulate TNFR2 Expression and Control Inflammation in Mycobacterial-Induced Pleurisy
Uysal Husnu, Chavez-Galan Leslie, Vesin Dominique, Blaser Guillaume, Benkhoucha Mahdia, Ryffel Bernhard, Quesniaux Valérie, Garcia Irene (2018), Transmembrane TNF and Partially TNFR1 Regulate TNFR2 Expression and Control Inflammation in Mycobacterial-Induced Pleurisy, in International Journal of Molecular Sciences, 19(7), 1959-1959.
Lipoarabinomannan Decreases Galectin-9 Expression and Tumor Necrosis Factor Pathway in Macrophages Favoring Mycobacterium tuberculosis Intracellular Growth
Chávez-Galán Leslie, Ramon-Luing Lucero, Carranza Claudia, Garcia Irene, Sada-Ovalle Isabel (2017), Lipoarabinomannan Decreases Galectin-9 Expression and Tumor Necrosis Factor Pathway in Macrophages Favoring Mycobacterium tuberculosis Intracellular Growth, in Frontiers in Immunology, 8, 1659.
Transmembrane Tumor Necrosis Factor Controls Myeloid-Derived Suppressor Cell Activity via TNF Receptor 2 and Protects from Excessive Inflammation during BCG-Induced Pleurisy
Chavez-Galan Leslie, Vesin Dominique, Uysal Husnu, Blaser Guillaume, Benkhoucha Mahdia, Ryffel Bernhard, Quesniaux Valérie F. J., Garcia Irene (2017), Transmembrane Tumor Necrosis Factor Controls Myeloid-Derived Suppressor Cell Activity via TNF Receptor 2 and Protects from Excessive Inflammation during BCG-Induced Pleurisy, in Frontiers in Immunology, 8, 999.
An Iron-Rich Diet Decreases the Mycobacterial Burden and Correlates With Hepcidin Upregulation, Lower Levels of Proinflammatory Mediators, and Increased T-Cell Recruitment in a Model of Mycobacterium
(2017), An Iron-Rich Diet Decreases the Mycobacterial Burden and Correlates With Hepcidin Upregulation, Lower Levels of Proinflammatory Mediators, and Increased T-Cell Recruitment in a Model of Mycobacterium, in Journal Injectious Disease, 907.
Self- observation and peer feedback as a faculty development approach for Problem-Based learning tutors: a program evaluation.
Garcia Irene (2017), Self- observation and peer feedback as a faculty development approach for Problem-Based learning tutors: a program evaluation., in Teach Learn Med, 2, 1.
Tumor Necrosis Factor and Its Receptors Are Crucial to Control Mycobacterium bovis Bacillus Calmette-Guerin Pleural Infection in a Murine Model
Chavez-Galan Leslie, Vesin Dominique, Segueni Noria, Prasad Pritha, Buser-Llinares Raphaële, Blaser Guillaume, Pache Jean-Claude, Ryffel Bernhard, Quesniaux Valérie F.J., Garcia Irene (2016), Tumor Necrosis Factor and Its Receptors Are Crucial to Control Mycobacterium bovis Bacillus Calmette-Guerin Pleural Infection in a Murine Model, in The American Journal of Pathology, 186(9), 2364-2377.
Innate myeloid cell TNFR1 mediates first line defence against primary Mycobacterium tuberculosis infection
(2016), Innate myeloid cell TNFR1 mediates first line defence against primary Mycobacterium tuberculosis infection, in Scientific report, 6, 22454.
Contribution of IL-36 versus IL-1 and TNF Pathways in Host Response to Mycobacterial Infection.
SEGUENI N. (2015), Contribution of IL-36 versus IL-1 and TNF Pathways in Host Response to Mycobacterial Infection., in PLosone, 1-21.
Control of Mycobacterial Infections in Mice Expressing Human Tumor Necrosis Factor (TNF) but Not Mouse TNF
OLLEROS M. et al. (2015), Control of Mycobacterial Infections in Mice Expressing Human Tumor Necrosis Factor (TNF) but Not Mouse TNF, in Infection and Immunity, 83(9), 3612-3623.
Much More than M1 and M2 Macrophages, There are also CD169(+) and TCR(+) Macrophages
CHAVEZ-GALAN L (2015), Much More than M1 and M2 Macrophages, There are also CD169(+) and TCR(+) Macrophages, in Frontiers in immunology, 6(263), 1-15.
Bacillus Calmette-Guerin Infection in NADPH Oxidase Deficiency: Defective Mycobacterial Sequestration and Granuloma Formation
DEFFERT C (2014), Bacillus Calmette-Guerin Infection in NADPH Oxidase Deficiency: Defective Mycobacterial Sequestration and Granuloma Formation, in PLOSPATHOGENS, 10(9), 1-14.
Tumor necrosis factor neutralization combined with chemotherapy enhances Mycobacterium tuberculosis clearance and reduces lung
BOURIGAULT M (2013), Tumor necrosis factor neutralization combined with chemotherapy enhances Mycobacterium tuberculosis clearance and reduces lung, in Am J Clin Exp Immuno, 124-134.
Low dose BCG infection as a model for macrophage activation maintaining cell viability
, Low dose BCG infection as a model for macrophage activation maintaining cell viability, in J Immunol Res.

Collaboration

Group / person Country
Types of collaboration
Dr. Sergei Nedospasov Russia (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. George Kollias Greece (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Valérie Quesniaux , CNRS, Orleans, France France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
23rd ECDO conference Poster Very low dose BCG is sufficient to activate macrophages maintaining cellular viability 07.10.2015 Genève, Switzerland Blaser Guillaume; Garcia-Gabay Irène; Vesin Marie-Dominique;
4th EUROPEAN CONGRESS OF IMMUNOLOGY Poster Low dose BCG is sufficient to activate macrophages maintaining mitochondria integrity 06.09.2015 Vienna, Austria Garcia-Gabay Irène; Vesin Marie-Dominique; Buser Llinares Raphaële; Blaser Guillaume;
15th International conference Tumor Necrosis Factor Poster Role of TNF in MDSC accumulation during mycobacterial pleural infection 20.05.2015 Ghent , Belgium Buser Llinares Raphaële; Mai Olleros Maria-Luisa; Garcia-Gabay Irène; Vesin Marie-Dominique; Blaser Guillaume;
4ème Conférence du MYCOCLUB Poster Absence of TNF promotes MDSC accumulation during pleural tuberculosis 06.05.2015 Marseille, France Blaser Guillaume; Garcia-Gabay Irène; Vesin Marie-Dominique; Buser Llinares Raphaële;


Associated projects

Number Title Start Funding scheme
118196 Role of tumor necrosis factor (TNF) in mycobacterial infections and inflammation 01.11.2007 Project funding
166662 Roles of TNF and TNF receptors in immunoregulation of host responses to pleural mycobacterial infections 01.04.2016 Project funding
166662 Roles of TNF and TNF receptors in immunoregulation of host responses to pleural mycobacterial infections 01.04.2016 Project funding
118196 Role of tumor necrosis factor (TNF) in mycobacterial infections and inflammation 01.11.2007 Project funding

Abstract

Tumor necrosis factor (TNF or TNF?) is a pleiotropic cytokine associated with the development of human immunopathologies, involved in physiological functions and host defense mechanisms against many pathogens. Anti-TNF therapies have shown their efficacy for the treatment of autoimmune inflammatory diseases such as rheumatoid arthritis and Crohn’s disease and are being expanded to treatment of other inflammatory diseases. However, complete TNF blockade has confirmed its critical role in the control of tuberculosis and other infections. Our previous work has been devoted to the study of the role of soluble TNF (solTNF) or membrane TNF (mTNF) in host immunity during the course of Mycobacterium bovis BCG and M. tuberculosis infections and inflammatory diseases. These studies have shown that mTNF can mediate several functions of solTNF during infection but exerts limited pathogenic activity during inflammatory liver diseases. According to this data, we have established that while total inhibition of TNF by non-selective inhibitors leads to fatal infection, selective inhibitors blocking only solTNF can be active in vivo in mice preventing acute inflammation but not inhibiting host immunity to mycobacterial infections. The identification of cellular sources of TNF begins to be defined, while cells responding to TNF mediating host protective immunity triggered by mycobacterial infections are unknown. This proposal explores interactions between TNF and TNFRs, mainly TNFR1, triggered by mycobacterial infection and investigates immunoregulatory and antimicrobial activities of TNF responses required for host immune responses against intracellular bacterial infection. Our first aim is the identification of specific cell types expressing TNFRs, responding to mycobacterial-induced TNF, and required for host protection mechanisms against mycobacteria. A combination of mouse models including mice deficient in TNFRs and bone-marrow chimeric mice will be used to determine whether TNF-responsive cells are from hematopoietic and/or nonhematopoietic origin and to identify cells relying on protection and sensitivity to the infection and associated immunopathology. As a model for interaction of TNF with TNFR1, we will explore host immunity in human TNF KI mice in which mouse TNF has been replaced by human TNF. The contribution of T cells and macrophages/neutrophils in host protection against M. bovis BCG and M. tuberculosis infections will be analyzed in mice with cell specific inactivation or activation of TNFR1. To understand underlying mechanisms involved in the interaction between TNF and TNF receptors, gene expression by microarray analysis will be carried out on selected infected lungs which may provide new targets for clinical intervention. Our second aim is the investigation of TNFR1 blockade as adjunctive therapy to treat virulent M. tubeculosis infection and underlying mechanisms. We will determine whether inactivation and blockade of TNFR1 improve lung immunopathology and bacterial clearance after M. tuberculosis chemotherapy and study the underlying mechanisms using gene expression profile by microarray analysis. These studies will extend our understanding of TNF-dependent host defense mechanisms based on the identification of cells and gene products that can be potential targets for designing new therapies for infectious diseases.
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