INSERM UMR 1152

Team 3
Innate Immunity and anti-infectious pulmonary defense
Coordinator : Pr Jean-Michel SALLENAVE (jean-michel.sallenave@inserm.fr)

At the surface of the epithelium and pulmonary alveoli, epithelial cells and innate immune cells (alveolar macrophages, NK cells, Innate lymphoid cells/ILCs..) interact,  through the production of surfactant, regulatory cytokines and antimicrobial molecules, to ensure a non- inflammatory regulatory phenotype . After infective or toxic stimuli exposure, these cells participate in a network to organize pro-inflammatory responses and to engage adaptive immunity to contain the  aggression and to insure the return to haemostasis. Our research group is mostly interested in the innate mechanisms put in place in this process and in the dysregulation of these control mechanisms, which could potentially explain the pathophysiology of some inflammatory disorders (chronic obstructive pulmonary diseases/COPD, cystic fibrosis, ventilator-associated pneumonia..)

Five main areas of investigation are currently being pursued in our team :

1) Study in vitro and in vivo of the role of Pseudomonas aeruginosa infections (an opportunistic pathogen in pulmonary nosocomial infection and in cystic fibrosis) in exacerbations of chronic lung diseases, including cystic fibrosis.  

2) In vitro and in vivo study of the mechanisms through which Influenza virus, a pathogen responsible for lung infections in seasonal flu or pandemic episodes can favour bacterial super-infections and induce disease exacerbations in chronic lung diseases.

3) Study of vaccination protocols to fight Pseudomonas aeruginosa infections

4) Study of host-pathogen interactions in COVID-19

5) Investigation of the molecular mechanisms of action of nanoparticles in the lung, in isolation or in conjunction with lung pathogens (S. aureus, P.aeruginosa, Influenza virus…), and their use as potential adjuvants in vaccination protocols.

The molecular processes, techniques, reagents, signalling pathways studied and used in this context include :

-mechanisms of Pathogen Associate Molecular Pattern/PAMP receptors activation, phagocytic processes, signal transduction  pathways ; role of epithelial type 2 serine proteases (TTSPs) during Influenza infection ; interactions between microbial virulence factors, innate immune  receptors  and epithelial channels (eg CFTR) ; study of endogenous antimicrobial molécules ; use of recombinant adenovirus vectors in over-expression protocols ; in vivo rodent infection models ;  RT-qPCR ; flow cytometry ; immuno-histochemistry ; proteomics.

Recent research publications :

-Prince L, Martín-Faivre L, Villeret B, Sanchez-Guzman D, Le Guen P, Sallenave JM, Garcia-Verdugo I. Eosinophils Recruited During Pulmonary Vaccination Regulate Mucosal Antibody Production. Am J Respir Cell Mol Biol. 2022 Oct 4. doi: 10.1165/rcmb.2022-0236OC. Online ahead of print.PMID: 36194580

-Villeret B, Ghinnagow R, Kheir S, Born-Bony M, Kolls JK, Garcia-Verdugo I, Sallenave JM. Pseudomonas Aeruginosa Lung Infection Subverts Lymphocytic Responses through IL-23 and IL-22 Post-Transcriptional Regulation. Int J Mol Sci. 2022 Jul 29;23(15):8427. doi: 10.3390/ijms23158427.

-Kheir S, Villeret B, Garcia-Verdugo I, Sallenave JM. IL-6-elafin genetically modified macrophages as a lung immunotherapeutic strategy against Pseudomonas aeruginosa infections. Mol Ther. 2022 Jan 5;30(1):355-369. doi: 10.1016/j.ymthe.2021.08.007. Epub 2021 Aug 8.

-Sallenave JM, Guillot L. Innate Immune Signaling and Proteolytic Pathways in the Resolution or Exacerbation of SARS-CoV-2 in Covid-19: Key Therapeutic Targets?

Front Immunol. 2020;11:1229. doi: 10.3389/fimmu.2020.01229. eCollection 2020.

-Villeret B, Solhonne B, Straube M, Lemaire F, Cazes A, Garcia-Verdugo I, Sallenave J-M. Influenza A virus pre-infection exacerbates Pseudomonas aeruginosa-mediated lung damage through increased MMP-9 expression, decreased elafin production and tissue resilience. Front Immunol. 2020, 11:117. doi: 10.3389/fimmu.2020.00117

-Sanchez-Guzman D, Le Guen P, Villeret B, Sola-Tapias N, Le Borgne R, Guyard A, Kemmel A, Crestani B, Sallenave JM, Garcia-Verdugo I. Silver nanoparticle-adjuvanted vaccine protects against lethal Influenza infection through inducing BALT and IgA-mediated mucosal Immunity. Biomaterials. 2019;217:119308. doi:10.1016/j.biomaterials.2019.119308. Epub 2019 Jun 26.

-Simonin J, Bille E, Crambert G, Noel S, Dreano E, Edwards A, Hatton A,  Pranke I, Villeret B, Cottart C-H, Vrel J-P, Urbach V, Baatallah N, Hinzpeter A, Golec A, Touqui L, Nassif X, Galietta L, Planelles G, Sallenave J-M, Edelman A, Sermet-Gaudelus I. Airway surface liquid acidification initiates host defense abnormalities in Cystic Fibrosis. Sci Rep. 2019;9:6516. doi: 10.1038/s41598-019-42751-4.

-Bastaert F, Kheir S, Saint-Criq V, Villeret B, Dang PM, El-Benna J, Sirard JC, Voulhoux R, Sallenave JM. Pseudomonas aeruginosa LasB Subverts Alveolar Macrophage Activity by Interfering with Bacterial Killing Through Downregulation of Innate Immune Defense, Reactive Oxygen Species Generation, and Complement Activation. Front Immunol. 2018 Jul 23;9:1675. doi: 10.3389/fimmu.2018.01675.

-Villeret B, Dieu A, Straube M, Solhonne B, Miklavc P, Hamadi S, Le Borgne R, Mailleux A, Norel X, Aerts J, Diallo D, Rouzet F, Dietl P, Sallenave JM, Garcia-Verdugo I. Silver Nanoparticles Impair Retinoic Acid-Inducible Gene I-Mediated Mitochondrial Antiviral Immunity by Blocking the Autophagic Flux in Lung Epithelial Cells. ACS Nano. 2018;12:1188-1202.

-Menou A, Flajolet P, Duitman JW, Justet A, Moog S, Jaillet M, Tabèze L, Garnier M, Mal H, Solhonne, B, Mordant P, Castier Y, Cazes A, Sallenave JM, Mailleux A, Crestani B. Human Airway Trypsin-like protease exerts potent anti-fibrotic action in vitro and in vivo. FASEB J, 2018 32:1250-1264.

-Saint-Criq V, Villeret B, Bastaert F, Kheir S, Hatton A, Cazes A, Xing Z, Sermet-Gaudelus I, Garcia-Verdugo I, Edelman A, Sallenave JM. Pseudomonas aeruginosa LasB protease impairs innate immunity in mice and humans by targeting a lung epithelial cystic fibrosis transmembrane regulator-IL-6-antimicrobial-repair pathway. Thorax, 2018; 73:49-61.

Lab members :

-Head of Team 3 : Jean-Michel Sallenave, Professor (PU-Ex) of Immunology, University of Paris Cité

-Dr I. Garcia-Verdugo, Associate Professor of Immunology, University of Paris Cité

-Pr P. Montravers, Professor (PU-PH, Hôpital Bichat, Paris)

-Pr A. Khalil, Professor (PU-PH, Hôpital Bichat, Paris)

-Dr Lydie Martin, ATER/post-doctoral fellow, University of Paris Cité

-Mrs Maëlys Born-Bony, PhD student, University of Paris Cité

-Mrs Lisa Prince, PhD student, University of Paris Cité

-Mrs Bérengère Villeret, Ingénieur d’études, University of Paris Cité

-Mrs Clémence Gaudin, Assistante Ingénieur d’Etudes, Vaincre la Mucoviscidose

-Mrs Clémentine Cornu, Master 2 student, University of Paris Cité