The purinergic receptor P2X7 and the NLRP3 inflammasome are druggable host factors required for SARS-CoV-2 infection

Frontiers in Immunology

Immunology

Véronique Saada¹  Marie Naigeon²  Cristina Di Primio³  Mario Costa⁴  Paola Quaranta⁵  Laura Falasca⁶  Franca Del Nonno⁶  Mauro Piacentini⁷  Roberta Nardacci⁸  Mauro Pistello⁹  Olivier Delelis^1,10  Frédéric Subra^1,10  Eric Deprez^1,10  Clémence Richetta^1,10  Vanessa Petit^1,11  David Ghez^1,12  Jean-Luc Perfettini^1,13  Déborah Lécuyer^1,13  Emie Gutierrez-Mateyron^1,13  Julia Delahousse^1,13  Aurélia Deva Nathan^1,13  Ali Mostefa-Kara^1,13  Désirée Tannous^1,14  Awatef Allouch^1,14  Angelo Paci^1,15  Pauline Maisonnasse^1,16  Romain Marlin^1,16  Roger Le Grand^1,16  Juliette Pascaud^1,17  Xavier Mariette^1,18  Nathalie Chaput^1,19 

[1] Department of Biology and Pathology, Gustave Roussy Cancer Center, Villejuif, France;Gustave Roussy Cancer Center, Villejuif, France;Université Paris-Saclay, Inserm, CNRS, Analyse Moléculaire, Modélisation et Imagerie de la Maladie Cancéreuse, Laboratoire d’Immunomonitoring en Oncologie, Villejuif, France;Université Paris-Saclay, Faculté de Pharmacie, Chatenay-Malabry, France;Institute of Neuroscience, Italian National Research Council, Pisa, Italy;Laboratory of Biology BIO@SNS, Scuola Normale Superiore, Pisa, Italy;Institute of Neuroscience, Italian National Research Council, Pisa, Italy;Laboratory of Biology BIO@SNS, Scuola Normale Superiore, Pisa, Italy;Centro Pisano Ricerca e Implementazione Clinical Flash Radiotherapy “CPFR@CISUP“, “S. Chiara” Hospital, Pisa, Italy;Institute of Neuroscience, Italian National Research Council, Pisa, Italy;Retrovirus Center, Department of Translational Research, Universita of Pisa, Pisa, Italy;National Institute for Infectious Diseases “Lazzaro Spallanzani”, Rome, Italy;National Institute for Infectious Diseases “Lazzaro Spallanzani”, Rome, Italy;Department of Biology, University of Rome “Tor Vergata”, Rome, Italy;National Institute for Infectious Diseases “Lazzaro Spallanzani”, Rome, Italy;UniCamillus - Saint Camillus International University of Health and Medical Sciences, Rome, Italy;Retrovirus Center, Department of Translational Research, Universita of Pisa, Pisa, Italy;Virology Operative Unit, Pisa University Hospital, Pisa, Italy;Université Paris-Saclay, ENS Paris-Saclay, CNRS UMR 8113, IDA FR3242, Laboratory of Biology and Applied Pharmacology (LBPA), Gif-sur-Yvette, France;Université Paris-Saclay, Inserm U1274, CEA, Genetic Stability, Stem Cells and Radiation, Fontenay-aux-Roses, France;Université Paris-Saclay, Inserm UMR1030, Laboratory of Molecular Radiotherapy and Therapeutic Innovation, Villejuif, France;Department of Hematology, Gustave Roussy Cancer Center, Villejuif, France;Université Paris-Saclay, Inserm UMR1030, Laboratory of Molecular Radiotherapy and Therapeutic Innovation, Villejuif, France;Gustave Roussy Cancer Center, Villejuif, France;Université Paris-Saclay, Inserm UMR1030, Laboratory of Molecular Radiotherapy and Therapeutic Innovation, Villejuif, France;Gustave Roussy Cancer Center, Villejuif, France;NH TherAguix SAS, Meylan, France;Université Paris-Saclay, Inserm UMR1030, Laboratory of Molecular Radiotherapy and Therapeutic Innovation, Villejuif, France;Gustave Roussy Cancer Center, Villejuif, France;Université Paris-Saclay, Faculté de Pharmacie, Chatenay-Malabry, France;Department of Biology and Pathology, Gustave Roussy Cancer Center, Villejuif, France;Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial Diseases (IMVA- HB/IDMIT), Fontenay-aux-Roses, France;Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial Diseases (IMVA- HB/IDMIT), Fontenay-aux-Roses, France;Assistance Publique, Hôpitaux de Paris (AP-HP), Hôpital Bicêtre, Le Kremlin Bicêtre, France;Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial Diseases (IMVA- HB/IDMIT), Fontenay-aux-Roses, France;Assistance Publique, Hôpitaux de Paris (AP-HP), Hôpital Bicêtre, Le Kremlin Bicêtre, France;Université Paris-Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France;Université Paris-Saclay, Inserm, CNRS, Analyse Moléculaire, Modélisation et Imagerie de la Maladie Cancéreuse, Laboratoire d’Immunomonitoring en Oncologie, Villejuif, France;Université Paris-Saclay, Faculté de Pharmacie, Chatenay-Malabry, France;Université Paris-Saclay, Gustave Roussy Cancer Center, CNRS, Stabilité Génétique et Oncogenèse, Villejuif, France;

关键词: NLRP3;    inflammasome;    P2X7;    SARS-CoV-2;    COVID-19;   

DOI  :  10.3389/fimmu.2023.1270081

 received in 2023-07-31, accepted in 2023-10-04,  发布年份 2023

来源: Frontiers

【 摘 要 】

Purinergic receptors and NOD-like receptor protein 3 (NLRP3) inflammasome regulate inflammation and viral infection, but their effects on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain poorly understood. Here, we report that the purinergic receptor P2X7 and NLRP3 inflammasome are cellular host factors required for SARS-CoV-2 infection. Lung autopsies from patients with severe coronavirus disease 2019 (COVID-19) reveal that NLRP3 expression is increased in host cellular targets of SARS-CoV-2 including alveolar macrophages, type II pneumocytes and syncytia arising from the fusion of infected macrophages, thus suggesting a potential role of NLRP3 and associated signaling pathways to both inflammation and viral replication. In vitro studies demonstrate that NLRP3-dependent inflammasome activation is detected upon macrophage abortive infection. More importantly, a weak activation of NLRP3 inflammasome is also detected during the early steps of SARS-CoV-2 infection of epithelial cells and promotes the viral replication in these cells. Interestingly, the purinergic receptor P2X7, which is known to control NLRP3 inflammasome activation, also favors the replication of D614G and alpha SARS-CoV-2 variants. Altogether, our results reveal an unexpected relationship between the purinergic receptor P2X7, the NLRP3 inflammasome and the permissiveness to SARS-CoV-2 infection that offers novel opportunities for COVID-19 treatment.

【 授权许可】

Unknown   
Copyright © 2023 Lécuyer, Nardacci, Tannous, Gutierrez-Mateyron, Deva Nathan, Subra, Di Primio, Quaranta, Petit, Richetta, Mostefa-Kara, Del Nonno, Falasca, Marlin, Maisonnasse, Delahousse, Pascaud, Deprez, Naigeon, Chaput, Paci, Saada, Ghez, Mariette, Costa, Pistello, Allouch, Delelis, Piacentini, Le Grand and Perfettini