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

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 Frontiers in Immunology frontiersin.org01 OPEN ACCESS EDITED BY Jagadeesh Bayry, Indian Institute of Technology Palakkad, India REVIEWED BY Talia H. Swartz, Icahn School of Medicine at Mount Sinai, United States Thomas Witzig, Mayo Clinic, United States *CORRESPONDENCE Jean-Luc Perfettini jean-luc.perfettini@gustaveroussy.fr RECEIVED 31 July 2023 ACCEPTED 04 October 2023 PUBLISHED 18 October 2023 CITATION Le´ cuyer D, Nardacci R, Tannous D, Gutierrez-Mateyron E, Deva Nathan A, Subra F, Di Primio C, Quaranta P, Petit V, Richetta C, Mostefa-Kara A, Del Nonno F, Falasca L, Marlin R, Maisonnasse P, Delahousse J, Pascaud J, Deprez E, Naigeon M, Chaput N, Paci A, Saada V, Ghez D, Mariette X, Costa M, Pistello M, Allouch A, Delelis O, Piacentini M, Le Grand R and Perfettini J-L (2023) The purinergic receptor P2X7 and the NLRP3 inflammasome are druggable host factors required for SARS-CoV-2 infection. Front. Immunol. 14:1270081. doi: 10.3389/fimmu.2023.1270081 COPYRIGHT © 2023 Le´ cuyer, 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. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. TYPE Original Research PUBLISHED 18 October 2023 DOI 10.3389/fimmu.2023.1270081 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