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International audience; The main objective of the work is the development of a new generation of field effect transistor sensors suitable for high sensitivity bio-sensing applications.

Tuberculosis (TB) is a major health problem requiring sustained immunity to inhibit Mycobacterium tuberculosis growth and appropriate antimicrobial therapy to prevent dissemination and drug resistance. Cell-mediated immune responses to M. tuberculosis involve the activation of cytokines such as Tumor Necrosis Factor (TNF) which is critical for granuloma formation and host resistance against TB. TNF inhibition, used as therapy for the treatment of inflammatory diseases, disrupts granuloma allowing replication of mycobacteria which may increase the efficacy of TB chemotherapy. To test this hypothesis mice infected with M. tuberculosis were treated with isoniazid (INH) and rifampicin (RMP) in the presence or absence of Enbrel, a soluble TNF receptor antagonist during three phases of M. tuberculosis infection. Inhibition of TNF with Enbrel augmented the efficacy of TB chemotherapy as shown by enhanced mycobacterial clearance from the lung of acute and established infection as well as in chronically infected mice. Furthermore, TNF inhibition significantly reduced lung pathology as compared to TB chemotherapy alone. Therefore, the experimental data suggest that TB chemotherapy may be more effective in the presence of a TNF inhibitor, which may be relevant to eradicate mycobacteria during chronic M. tuberculosis infection or reactivation.

Les phosphatidyl-myo-inositol mannosides sont des précurseurs biosynthétiques de lipoarabinomannanes et lipomanannes qui sont des composants de la paroi des bactéries du genre Mycobacterium. Les phosphatidyl-myo-inositol dimannosides (PIM2) et hexamannosides (PIM6) sont les deux formes les plus abondantes de PIM chez les M. tuberculosis et M.bovis (BCG). La synthèse complète des différents PIMs a été rapportée. Nous avons déjà démontré que les fractions de PIM6 ont une activité inhibitrice sur la production de cytokines pro-inflammatoires induites par le LPS dans des macrophages primaires. L’activité inhibitrice des PIMs est également retrouvée avec des PIMs synthétiques.Nous nous sommes intéressés au mode d’action de ces molécules : tout d’abord en étudiant la possibilité d’une activation alternative des macrophages et en étudiant également les voies de signalisation intracellulaire impliquées dans cette inhibition.Dans un deuxième temps nous avons suivi l’interaction PIM2 – macrophage grâce à deux PIM2 traceur, l’un couplé à une biotine et l’autre à une molécule de TRITC.Enfin nous avons déterminé les propriétés anti-inflammatoires de différents analogues de PIM2 in vitro sur des cultures de macrophages stimulées au lipopolysaccharide, puis in vivo dans un modèle de challenge modéré au lipopolysaccharide chez la souris.L’activité anti-inflammatoire des PIM en réponse au LPS pourrait être une thérapie intéressante pour bloquer les réponses aux endotoxines, diminuer l’expression des cytokines dans le cadre des chocs toxi-infectieux, et peut être plus largement dans d’autres pathologies inflammatoires.

Tumor necrosis factor (TNF) is required in the control of infection with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. TNF is essential and non-redundant for forming microbiocidal granulomas, and cannot be replaced by other members of the TNF family. We established a model of latent Mtb infection in mice, allowing investigation of the reactivation of latent Mtb as observed in patients receiving TNF-neutralizing therapy used in rheumatoid arthritis and Crohn's disease. Antibody neutralization of TNF is able to reactivate clinically silent Mtb infection. Using mutant mice expressing solely membrane, but not soluble TNF, we demonstrated that membrane TNF is sufficient to control acute Mtb infection. Therefore, we hypothesize that TNF-neutralizing therapy, sparing membrane TNF, may have an advantage as compared to complete neutralization. In conclusion, endogenous TNF is critical for the control of tuberculosis infection. Genetic absence or pharmacological neutralization of TNF results in uncontrolled infection, while selective neutralization might retain the desired anti-inflammatory effect but reduce the infectious risk.

International audience; The initial objective of this work was to examine the effects of an antibody (Anti-G21V) directed against the second extracellular loop of human heart 5-HT4 receptors expressed in Chinese hamster ovary (CHO) cells. The antibody anti-G21V had no effect upon either basal cAMP- or 5-HT-evoked increases in cAMP in CHO cells, whereas it had shown an agonist-like effect in COS-7 cells. Analysis of agonist fractions of h5-HT4(e) receptors in CHO and COS-7 cells revealed that equilibrium constant could underlie the different responses of the receptor toward the anti-G21V antibody. Therefore, different expression systems could give rise to functional differences in 5-HT4 receptor behavior.