Equipe d’Accueil : Biology of phagocytes, infection and immunity
Intitulé de l’Unité : Institut Cochin,Inserm U1016-CNRS UMR8104-Université Paris Cité
Nom du Responsable de l’Unité : Florence Niedergang
Nom du Responsable de l’Équipe : Florence Niedergang
Adresse : 22, rue Méchain, 75014 Paris
Responsable de l’encadrement : Ignacio Garcia-Verdugo
Tél : 0140516406 Fax : ……………………… E-mail: ignacio.garcia-verdugo@inserm.fr
Résumé du projet
Introduction. Alveolar macrophages (AMs) are tissue-resident immune cells that play a central role in maintaining pulmonary homeostasis and protecting the lungs against respiratory pathogens. They detect invading microorganisms through pattern recognition receptors (PRRs), leading to the production of pro-inflammatory cytokines and interferons, and eliminate pathogens through phagocytosis. AM development and maintenance critically depend on signals provided by lung epithelial cells (ECs), particularly the growth factor GM-CSF. While the role of EC in maintaining AM homeostasis is well established, much less is known about their ability to regulate macrophage immune functions during viral infection. We have previously shown that soluble factors produced by EC enhance the antiviral activity of AM. Since influenza virus primarily infects EC, infection-induced changes in epithelial cell secretions may profoundly influence macrophage function. Indeed, following influenza virus infection, AM can acquire a dysfunctional phenotype characterized by impaired cytokine production and reduced phagocytic capacity, thereby increasing susceptibility to secondary bacterial infections. However, the contribution of EC-derived soluble mediators to this dysfunction remains poorly understood.
We hypothesize that influenza virus infection alters the secretory profile of EC, thereby modulating AM activation and antiviral functions. The objective of this project is therefore to identify the epithelialderived factors and signaling pathways that regulate macrophage responses during influenza virus infection.
Methods. Human epithelial cell lines and primary mouse lung epithelial cells will be infected with influenza virus to generate conditioned media from infected and uninfected cultures. These conditioned media will be used to stimulate primary AM or macrophage cell lines. Macrophages will subsequently be infected with influenza virus or stimulated with PRR agonists that mimic viral infection. Cytokine and interferon expression will be quantified by RT-qPCR and ELISA, while macrophage activation markers will be analyzed by flow cytometry.
To identify EC-derived soluble mediators, conditioned media will be fractionated by size-exclusion filtration and analyzed by mass spectrometry. Comparative proteomic analysis of conditioned media from wild-type and viral sensing-deficient epithelial cells will identify candidate molecules, which will subsequently be validated in vitro and in vivo
Expected outcomes. This project aims to elucidate the molecular mechanisms by which EC regulate AM immune functions under both homeostatic and infectious conditions. A better understanding of epithelial-macrophage crosstalk during influenza virus infection may reveal novel mechanisms underlying virus-induced immune dysregulation and provide new targets for therapies or vaccines designed to enhance respiratory immunity.
Dernières Publications en lien avec le projet :
Martín-Faivre et al (2025). Pulmonary delivery of silver nanoparticles prevents influenza infection by recruiting and activating lymphoid cells. Biomaterials 312:122721.
Faure-Dupuy et al. (2024). ARL5b inhibits human rhinovirus 16 propagation and impairs macrophage-mediated bacterial clearance. EMBO Rep. 25:1156-1175.
Jubrail et al. (2020). Arpin is critical for phagocytosis in macrophages and is targeted by human rhinovirus. EMBO Rep. 21:e47963.
Villeret et al. (2018). Silver Nanoparticles Impair Retinoic Acid-Inducible Gene IMediated Mitochondrial Antiviral Immunity by Blocking the Autophagic Flux in Lung Epithelial Cells. ACS Nano.12:1188.
Ce projet s’inscrit-il dans la perspective d’une thèse :
oui X non o
si oui type de financement prévu : Ecole Doctorale
Ecole Doctorale de rattachement : Microorganismes et Infection