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Roles of TNF and TNF receptors in immunoregulation of host responses to pleural mycobacterial infections

English title Roles of TNF and TNF receptors in immunoregulation of host responses to pleural mycobacterial infections
Applicant Garcia-Gabay Irène
Number 166662
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 01.04.2016 - 30.09.2018
Approved amount 223'450.00
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Keywords (2)

TNF, TNF receptors, BCG, M. tuberculosis, ; Pleural tuberculosis, mesothelial cell

Lay Summary (French)

Lead
Titre du projet de recherche Les rôles du «Tumor Necrosis Factor» (TNF) et ses récepteurs dans l’immunorégulation des réponses anti-mycobactériennes lors d’une infection pleurale Lead Le TNF est une cytokine impliquée dans le développement des certaines maladies chroniques ainsi que dans la protection contre des agents pathogènes tels que des mycobactéries. Des traitements anti-inflammatoires qui utilisent des anti-TNF ont montré leur efficacité dans le cas des maladies auto-immunes telles que l’arthrite rhumatoïde. Cependant, les risques associés à l’inhibition du TNF dus à la diminution de la protection immune contre des mycobactéries, peuvent engendrer la réactivation d’une tuberculose latente, pulmonaire ou extra-pulmonaire notamment dans la plèvre.
Lay summary

Contenu et objectifs du travail de recherche
Ces dernières années, les connaissances du rôle des cytokines sur l’immunité contre les mycobactéries ont permis de définir l’activité de différentes formes moléculaires du TNF (transmembranaire et soluble), de déterminer ses sources cellulaires, et de caractériser l’interaction avec ses récepteurs pour enclencher la protection chez l’individu infecté. Par contre, l’immunopathologie de l’infection pleurale par mycobactéries reste relativement inconnue à ce jour.
Le projet porte sur l’exploration des mécanismes cellulaires et moléculaires impliqués dans l’infection pleurale à mycobactéries et dans sa résolution. Nous utilisons un modèle murin d’infection pleurale aux mycobactéries, Mycobacterium bovis BCG et M. tuberculosis, qui nous permettra la caractérisation des cellules recrutées dans la cavité pleurale et leur activité dans la réponse immune. En utilisant de modèles d’animaux spécifiques pour l’expression des récepteurs TNFR1 ou TNFR2 ou du TNF, nous envisageons d’identifier les cellules qui répondent au TNF et sur lesquelles reposerait l’efficacité de l’immunité intra pleurale et la résolution de l’infection.

Contexte scientifique et social du projet de recherché
Le projet relève de la recherche fondamentale sur des infections peu étudiées chez l’animal et chez l’homme. Nous allons mieux comprendre la pathologie générée par l’infection bactérienne de la plèvre, ses conséquences et sa résolution afin de pouvoir envisager des traitements adéquats, basés sur nos connaissances du système TNF, qui nous permettra de mieux cibler des populations cellulaires impliquées dans la pathologie et la guérison.

Mots-clés
Tumor Necrosis Factor ou TNF, récepteurs du TNF, BCG, Mycobacterium tuberculosis, infection pleurale, cellules mésothéliales.


Direct link to Lay Summary Last update: 01.04.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
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, 1-15.
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, 1-15.
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.
Segueni Noria, Benmerzoug Sulayman, Rose Stéphanie, Gauthier Amandine, Bourigault Marie-Laure, Reverchon Flora, Philippeau Amandine, Erard François, Le Bert Marc, Bouscayrol Hélène, Wachter Thierry, Garcia Irène, Kollias George, Jacobs Muazzam, Ryffel Bernhard, Quesniaux Valerie F.J. (2016), Innate myeloid cell TNFR1 mediates first line defence against primary Mycobacterium tuberculosis infection., in Scientific Reports, 6(1), 22454-22454.
Low Dose BCG Infection as a Model for Macrophage Activation Maintaining Cell Viability
Chávez-Galán Leslie, Vesin Dominique, Martinvalet Denis, Garcia Irene (2016), Low Dose BCG Infection as a Model for Macrophage Activation Maintaining Cell Viability, in Journal of Immunology Research, 2016, 1-17.

Collaboration

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

Associated projects

Number Title Start Funding scheme
146833 Roles of TNF receptors in immunoregulation of responses to mycobacterial infections 01.04.2013 Project funding
146833 Roles of TNF receptors in immunoregulation of responses to mycobacterial infections 01.04.2013 Project funding

Abstract

Tumor necrosis factor (TNF) is a pleiotropic cytokine associated with the development of human immunopathologies, involved in physiological functions and host defense mechanisms against many pathogens. Our previous work has been devoted to the study of the role of soluble TNF (solTNF) and trasmembrane TNF (tmTNF) in host immunity during the course of Mycobacterium bovis BCG and M. tuberculosis infections and inflammatory diseases, mainly liver diseases. Our studies have shown that tmTNF can mediate some protective activities as solTNF during infection but does not exert detrimental activity during inflammatory liver diseases. According to this data, we have proposed 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.In human, 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 (TB) as latent TB can be reactivated in patients under anti-TNF therapy. Extra-pulmonary TB has been observed under anti-TNF treatment and pleural effusion occurs frequently, however, the pathophysiology of the disease is still not clear. On the basis of our preliminary results, presented as a manuscript, this proposal explores the cellular mechanisms involved in pleural mycobacterial infection and resolution of the immune response by using a model of mycobacterial-induced pleurisy and considering that TNF and TNFR pathways are crucial participants for host protection but cellular mechanisms are still not clear. We will investigate interactions between TNF and cells expressing TNFRs triggered by mycobacterial infection in the pleural cavity and 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 subpopulations that accumulate in the pleural cavity during infection and resolution of mycobacterial-induced pleurisy. We will characterize cellular activities following the hypothesis that these cells can be manipulated by cytokines with benefits for disease outcome. We aim to identify cell types expressing TNFRs, responding to mycobacterial-induced TNF, and required for host protection mechanisms against pleural mycobacterial infection. 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 pleural infection and associated immunopathology. We will investigate the participation of visceral and parietal mesothelial cells in host immunity against mycobacterial pleural infection. These studies will extend our understanding of TNF-dependent host defense mechanisms based on the identification of cell subpopulation activities that can be potential targets for designing new therapies for infectious diseases and in particular for pleural tuberculosis.
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