Institut Necker Enfants Malades

Focus

The main focus of my laboratory is to investigate the regulation of innate immune sensors such as Toll-like receptors in dendritic cells

Introduction

Toll-like receptors (TLRs) recognize microbial products and play an essential role in innate and adaptive immunity. TLRs are divided in two families: membrane TLRs which sense the presence of proteins and lipids from bacteria and intracellular TLRs (TLR3, 7 and 9) localized in endosomes which, engage single stranded, double stranded RNA and methylated CpG DNA respectively from pathogens. In the absence of stimulation, intracellular TLRs are retained in the endoplasmic reticulum (ER) together with another ER resident protein, UNC93B1. Following nucleic acids sensing, intracellular TLRs traffic to endosomes where they require proteolytic cleavage to be functional and recruit the adaptor proteins MyD88 and TRIF. Their signalling which, leads to the production of pro-inflammatory cytokines and cell surface expression of co-stimulatory molecules, is essential to induce adaptive immunity in dendritic cells (DCs). The molecular chaperone UNC93B1 is essential for TLRs folding and trafficking and also set their activation threshold. Indeed, excessive TLR7 or TLR9 signalling can lead to autoimmunity and death. Thus, characterizing new factors involved in TLRs signalling is crucial in determining what influences the outcome of the immune response. The aim of our work is to further investigate how intracellular TLR trafficking and signalling are regulated at the steady state and following pathogen infection in DCs.

Research objectives

The overall goals are:

To study spatio-temporal signalling of endo-lysosomal TLRs signalling
To identify new proteins controlling TLRs trafficking and signalling
To investigate TLRs activation and regulation in ER stress, cancer and pathogen infection

2020

Tohme M, Maisonneuve L, Achour K, Dussiot M, Manoury B. TLR7 trafficking and signaling in B cells is regulated by the MHC-II associated invariant chain. 2020 Mar 10;133(5):jcs236711. doi: 10.1242/jcs.236711.

Jason Cosgrove, Mario Novkovic, Stefan Albrecht, Natalia Pikor, Zhaokun Zhou, Lucas Onder, Urs Mörbe, Jovana Cupovic, Helen Miller, Kieran Alden, Anne Thuery, Peter O'Toole, Rita Pinter, Simon Jarrett, Emily Taylor, Daniel Venetz, Manfred Heller, Mariagrazia Uguccioni, Daniel Legler, Charles Lacey, Andrew Coatesworth, Wojciech Polak, Tom Cupedo, Bénédicte Manoury, Marcus Thelen, Jens Stein, Marlene Wolf, Mark Leake, Jon Timmis, Burkhard Ludewig, and Mark Coles. B-cell Zone Reticular Cell Microenvironments Shape CXCL13 Gradient Formation. 2020 Nature communication In press

2019

Manoury B, De Berardinis P. Editorial : targeted antigen delivery : bridging innate and adaptive immunity. Front Immunol 2019 Mar 5;10:368. doi: 10.3389/fimmu

2018

E Aksoy, L Saveanu and B Manoury. The isoforms selective roles of PI3K in dendritic cell biology and function. Front Immunol 2018 Nov 15;9:2574. doi: 10.3389/fimmu.2018.02574.

Maatouk L, Compagnion AC, Carillo-de Sauvage MA, Bemelmans A, Trawik BN, Cirotteau V, Tohme M, Beke A, Trichet M, Bazin V, Brouillet E, Ransohoff RM, Tronche F, Manoury B, Vyas S. TLR9 activation via microglial glucocorticoid receptors contributes to degeneration of midbrain dopamine neurons. Nat Commun 2018 Jun 22 ;9 (1)2450 doi: 10.1038/s41467-018-04569-y.

2017

Nunes-Hasler P, Maschaladi S, Lippens C, Castelbou C, l Bouvet S, Guido D, Bassoy ES, Page N, Merkler D, Hugues S, Martinvalet D, Manoury B, Demaurex N. STIM1 promotes migration, phagosomal maturation and antigen cross- presentation in dendritic cells. 2017 Nat Commun Nov 24;8(1):1852. doi: 10.1038/s41467-017-01600-6.

Maschalidi S, Nunes-Hasler P, Nascimento C, Salent I, Lannoy V, Garfa-Traore M, Cagnard N, Sepulveda FE, Vargas P, Lennon-Duménil AM, van-Endert P, Capiod T, Demaurex N, Darasse-Jèze G, Manoury B. UNC93B1 interacts with the calcium sensor STIM1 for efficient antigen cross-presentation in dendritic cells. 2017 Nat Commun. Nov 21;8(1):1640. doi: 10.1038/s41467-017-01601-5.

Babdor J, Descamps D, Adiko AC, Tohmé M, Maschalidi S, Evnouchidou I, Vasconcellos LR, De Luca M, Mauvais FX, Garfa-Traore M, Brinkmann MM, Chignard M, Saveanu L*, Manoury B*. IRAP+ endosomes restrict TLR9 activation and signaling. 2017 Nat Immunol May;18(5):509-518doi: 10.1038/ni.3711. *Co-last and corresponding authors.
This article was chosen for the cover of Nature Immunology.

Smith N, Pietrancosta N, Davidson S, Dutrieux J, Chauveau L, Cutolo P, Dy M, Scott-Algara D, Manoury B, Zirafi O, McCort-Tranchepain I, Durroux T, Bachelerie F, Schwartz O, Münch J, Wack A, Nisole S, Herbeuval JP. Natural amines inhibit activation of human plasmacytoid dendritic cells through CXCR4 engagement. 2017 Nat Commun. Feb 9;8:14253. doi: 10.1038/ncomms14253.

2016

Duvallet E, Boulpicante M, Yamazaki T, Daskalogianni C, Prado Martins R, Baconnais S, Manoury B, Fahraeus R, Apcher S. exosome-driven transfer of tumor-associated Pioneer Translation Products (TA-PTPs) for the MHC class I cross-presentation pathway. 2016 Oncoimmunology Jun 21;5(9):e1198865.

Rasid O, Mériaux V, Khan EM, Borde C, Ciulean IS, Fitting C, Manoury B, Cavaillon JM, Doyen N. Cathepsin B-deficient mice resolve leishmania major inflammation faster in a T cell-dependent manner. 2016 PLoS Negl Trop Dis. May 16;10(5):e0004716. doi: 10.1371/journal.pntd.0004716.

2015

Tohmé M and Manoury B. Invariant chain is a new chaperone for TLR7 in B cells. 2015 Molecular Immunology Jul 18. pii: S0161-5890(15)00436-8

Brahimi-Horn MC, Lacas-Gervais S, Adaixo R, Ilc K, Rouleau M, Notte A, Dieu M, Michels C, Voeltzel T, Maguer-Satta V, Pelletier J, Ilie M, Hofman P, Manoury B, Schmidt A, Hiller S, Pouysségur J, Mazure NM. 2015 Local mitochondrial-endolysosomal microfusion cleaves the voltage-dependent anion channel 1 to promote survival in hypoxia. 2015 Mol Cell Biol Feb 17: 01402-14.

Daskalogianni C, Pyndiah S, Apcher S, Mazars A, Manoury B, Ammari N, Nylander K, Voisset C, Blondel M, Fåhraeus R. Epstein-Barr virus–encoded EBNA1 and ZEBRA : targets for therapeutic strategies against EBV-carrying cancers. 2015 J Pathol Jan;235(2):334-41.

2014

Khan ME, Borde C, Rocha EP, Mériaux V, Maréchal V, Guerrero P, Goyard S, Cavaillon JM, Manoury B, Doyen N. TLR9 activation is triggered by the excess of stimulatory vs inhibitory motifs present in Trypanosomatidae DNA. 2014 PLoS Negl Trop Dis Nov 13;8(11):e3308.

Wang H, Flannery SM, Dickhöfer S, Huhn S, George J, Kubarenko AV, Lascorz J, Bevier M, Willemsen J, Pichulik T, Schafmayer C, Binder M, Manoury B, Paludan SR, Alarcon Riquelme M, Bowie AG, Försti A, Weber AN. A coding IRAK2 variant compromises TLR signaling and is associated with colorectal cancer survival. 2014 J Biol Chem. Aug 15;289(33):23123-31.

Colak E, Leslie A, Zausmer K, Khatamzas E, Kubarenko AV, Pichulik T, Klimosch SN, Mayer A, Siggs O, Hector A, Fischer R, Klesser B, Rautanen A, Frank M, Hill AV, Manoury B, Beutler B, Hartl D, Simmons A, Weber AN. RNA and imidazoquinolines are sensed by distinct TLR7/8 ectodomains sites resulting in functionnaly disparate signaling events. 2014 J Immunol Jun 15;192(12):5963-73.

Benmohamed F, Medina M, Wu YZ, Maschalidi S, Jouvion G, Guillemot L, Chignard M, Manoury B, Touqui L. Toll-like receptor 9 deficiency protects mice against pseudomonas aeruginosa lung infection. 2014. PLoS One. 2014 Mar 4;9(3):e90466

Tohme M, Manoury B. Intracellular Toll-like receptor recruitment and cleavage in endosomal/lysosomal organelles. 2014 Methods in Enzymology 535:141-7.

2013

Apcher S, Millot G, Daskalogianni C, Scherl A, Manoury B, Fåhraeus R. Translation of pre-spliced RNAs in the nuclear compartment generates peptides for the MHC class I pathway. Proc Natl Acad Sci U S A. 2013 Oct 29;110(44):17951-6

Manoury B. Proteases : essential Actors in Processing Antigens and Intracellular Toll-Like Receptors. Front Immunol. 2013 Sep 24;4:299.

Tohme M, Maschalidi S, Manoury B. In Vitro Digestion With Proteases Producing MHC Class II Ligands. 2013 Methods Mol Biol 960: 509-515.

2012

Descamps D, Manoury B, Sallenave JM. Le TLR5 : un partenaire crucial pour la phagocytose et l’élimination de Pseudomonas aeruginosa par les macrophages alvéolaires impliquant l’IL1-b et l’asparagine endopeptidase. 2012 Brève SFI Juin n°126.

Maschalidi S, Hässler S, Blanc F, Sepulveda F, Tohme M, Chignard M, van Endert P, Si-Tahar M, Descamps D and Manoury B. Asparagine Endopeptidase Controls Anti-Influenza Virus Immune Responses through TLR7 Activation. 2012 PLOS Pathog. Aug;8(8):e1002841.

Apcher S, Manoury B, Fahraeus R. The role of mRNA translation in direct MHC class I antigen presentation. 2012 Current Opinion in Immunology 24 :71-76.

Weimershaus M, Maschalidi S, Sepulveda F, Manoury B, Van endert P, Saveanu L. Functional and Cell Biological impact of Insulin-Response Aminopeptidase in MHC Class I cross-presentation. 2012 J. Immunol. Feb 15;188(4):1840-6.

Descamps D, Le Gars M, Balloy V, Barbier D, Maschalidi S, Chignard M, Ramphal R, Manoury B*, Sallenave JM*. TLR5 activation, IL-1β signaling and asparagine endopeptidase activity: a new pathway for alveolar macrophage phagocytosis and bacterial killing. 2012 Proc Natl Acad Sci U S A 109:1619-24. *Corresponding authors.

2011

Guery L, Benikhlef N, Gauthier T, Paul C, Dufour E, Jacquel A, Cally R, Manoury B, Vanden Berghe T, Vandenabeele P, Droin N and Solary E. Fine-tuning nucleophosmin in macrophage differentiation and activation. 2011. Blood Oct 27;118(17):4694-704.

Manoury B.TLR9 regulation by proteolysis: a friend or a foe. 2011 Eur J Immunol. Aug;41(8):2142-4.

Apcher S, Daskalogianni C, Lejeune F, Manoury B, Imhoos G, Heslop L, Fahraeus R. Major source of antigenic peptides for the MHC class I pathway is produced during the pioneer round of mRNA translation. 2011 Proc Natl Acad Sci U S A. Jul 12;108(28):11572-7.

2010

Apcher S, Daskalogianni C, Manoury B, Fahraeus R. Epstein Barr virus-encoded EBNA1 interference with MHC class I antigen presentation reveals a close correlation between mRNA translation initiation and antigen presentation. 2010 PLoS Pathog. Oct 14;6(10).

2009

Sepulveda F, Maschalidi S, Colisson R, Heslop L, sakka E, Ghirelli, C, Lennon-dumenil AM, Amigorena S, Cabanie L and Manoury B. Critical Role for Asparagine Endopeptidase in endocytic TLR signalling in dendritic cells. 2009 Immunity Nov 20, 31 731-748.
In the same issue, News and views by van Endert P. Toll-like receptor 9: AEP takes control. 2009 Immunity Nov 20, 31 696-698.

Bénédicte Manoury studied biochemistry and cell biology at University Pierre and Marie Curie in Paris. She was awarded a PhD in Immunology at University René Descartes and an EMBO long-term fellowship to do her post-doctorate in the laboratory of Pr C Watts in Dundee studying antigen presentation in dendritic cells. She came back to Paris to start her own team in 2004 supported by an AVENIR grant (INSERM). She is now the head of the group « Immune response and Danger signals » at Institut Necker Enfants Malades where she investigates Toll-like receptor activation in cancer and infectious diseases.

Permanent researcher