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

Front Immunol. 2023 Oct 18:14:1270081. doi: 10.3389/fimmu.2023.1270081. eCollection 2023.

Abstract

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.

Keywords: COVID-19; NLRP3; P2X7; SARS-CoV-2; inflammasome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19 Drug Treatment
  • COVID-19*
  • Humans
  • Inflammasomes* / metabolism
  • Inflammation
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • NLR Proteins
  • Receptors, Purinergic
  • SARS-CoV-2 / metabolism

Substances

  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLR Proteins
  • Receptors, Purinergic

Supplementary concepts

  • SARS-CoV-2 variants

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by funds from Agence Nationale de la Recherche (ANR-10-IBHU-0001, ANR-10-LABX33, ANR-11-IDEX-003-01 and ANR Flash COVID-19 “MacCOV”), Fondation de France (alliance “tous unis contre le virus”), Electricité de France, Fondation Gustave Roussy, Institut National du Cancer (INCa 9414 and INCa 16087), The SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE), Fédération Hopitalo-Universitaire (FHU) CARE (Cancer and Autoimmunity Relationships) (directed by XM, Hôpital Bicêtre, AP-HP) and Université Paris-Saclay (to J-LP), MIUR (PRIN 2012 and FIRB), the ministry of Health of Italy “Ricerca Corrente” and “Ricerca Finalizzata” (COVID-2020-12371817 and COVID-2020-12371675) (to MPia), REACTing and the Fondation pour la Recherche Médicale (AM-CoV-Path program) (to RL). We thank the Domaine d’Intérêt Majeur (DIM, Paris, France) “One Health” and “Immunothérapies, auto-immunité et Cancer” (ITAC) for its support. The Infectious Disease Models and Innovative Therapies research infrastructure (IDMIT) is supported by the “Programmes Investissements d’Avenir” (PIA), managed by the ANR under references ANR-11-INBS-0008 and ANR-10-EQPX-02-01. DL and DT are recipients of PhD fellowships from LabEx LERMIT and Agence Nationale de la Recherche et de la Technologie (ANRT, Cifre#2019/0639), respectively. ADN and EG-M are recipients of PhD fellowships from French Ministry of Higher Education, Research and Innovation. AM-K is recipient of PhD fellowship from Ecole et Loisir.