TY - JOUR
T1 - Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells
AU - Planès, R. mi
AU - Pinilla, Miriam
AU - Santoni, Karin
AU - Hessel, Audrey
AU - Passemar, Charlotte
AU - Lay, Kenneth
AU - Paillette, Perrine
AU - Valadão, Ana-Luiza Chaves
AU - Robinson, Kim Samirah
AU - Bastard, Paul
AU - Lam, Nathaniel
AU - Fadrique, Ricardo
AU - Rossi, Ida
AU - Pericat, David
AU - Bagayoko, Salimata
AU - Leon-Icaza, Stephen Adonai
AU - Rombouts, Yoann
AU - Perouzel, Eric
AU - Tiraby, Michèle
AU - Zhang, Qian
AU - Cicuta, Pietro
AU - Jouanguy, Emmanuelle
AU - Neyrolles, Olivier
AU - Bryant, Clare E.
AU - Floto, Andres R.
AU - Goujon, Caroline
AU - Lei, Franklin Zhong
AU - Martin-Blondel, Guillaume
AU - Silva, Stein
AU - Casanova, Jean-Laurent
AU - Cougoule, C. line
AU - COVID Human Genetic Effort
AU - Reversade, Bruno
AU - Marcoux, Julien
AU - Ravet, Emmanuel
AU - Meunier, Etienne
N1 - Funding Information:
This project was funded by grants from the Fondation pour la Recherche Médicale (F.R.M.) and the ERC StG (INFLAME) to E.M. the ERC StG (ANTIViR) to C.G. and the French Ministry of Health with the participation of the Groupement Interrégional de Recherche Clinique et d'Innovation Sud-Ouest Outre-Mer (PHRCI 2020 IMMUNOMARK-COV) to G.-M.B. The ASB3 structure is supported by LABEX, Investissement d'Avenir and foundation Bettencourt grants to O.N. M.P. and R.P. were, respectively, funded by a CIFRE PhD fellowship and a research grant from InvivoGen. S.B. is supported by a PhD fellowship from Mali Ministry of Education and from the FRM (FDT 12794). S.A.L.-I. is supported by a Vaincre La Mucoviscidose (VLM) PhD fellowship. We thank the following organizations for the highly valuable contribution of the COVID-BioToul biobank: the CRB TBR, the Clinical Research Center 1436, and the Delegation for clinical research and innovation of the Toulouse University Hospital. The authors acknowledge Celine Beronne and Flavie Moreau of the IPBS Institute Animal Facility Level 3 (ASB3) members for their help regarding the operating and technical procedures. The authors acknowledge BEI for SARS-CoV-2 material transfer, including SARS-CoV-2 variants, NSP5- and NSP5C145A-expressing plasmids, and antibodies. The authors deeply acknowledge all patients for their willingness and support in contributing and sharing samples for academic research. Biorender.com was used to generate some graphical figures. Life Science Editors performed language editing. Funders had no influence on how the project was conducted. E.M. and R.P. conceptualized the study. E.M. R.P. E.R. M.P. K.S. A.H. and C.P. designed the methodology. R.P. M.P. K.S. A.H. C.P. P.P. A.-L.C.V. I.R. N.L. R.F. D.P. S.-A.L.-I. Y.R. C.G. C.C. and J.M. performed the experiments. E.M. R.P. C.C. G.M.-B. and E.R. conducted the analysis. K.L. K.S.R. E.P. M.T. O.N. F.Z.L. G.M.-B. C.E.B. A.R.F. P.C. J.-L.C. B.R. E.R. E.P. C.G. and M.T. provided critical reagents and essential medical, technological, and infrastructure access and support. E.M. R.P. and E.R. wrote the manuscript with input from all authors. E.M. O.N. E.P. and M.T. acquired and provided funding. The authors declare no competing interests.
Funding Information:
This project was funded by grants from the Fondation pour la Recherche Médicale (F.R.M.) and the ERC StG (INFLAME) to E.M., the ERC StG (ANTIViR) to C.G., and the French Ministry of Health with the participation of the Groupement Interrégional de Recherche Clinique et d’Innovation Sud-Ouest Outre-Mer ( PHRCI 2020 IMMUNOMARK-COV) to G.-M.B. The ASB3 structure is supported by LABEX , Investissement d’Avenir and foundation Bettencourt grants to O.N. M.P. and R.P. were, respectively, funded by a CIFRE PhD fellowship and a research grant from InvivoGen . S.B. is supported by a PhD fellowship from Mali Ministry of Education and from the FRM ( FDT 12794 ). S.A.L.-I. is supported by a Vaincre La Mucoviscidose (VLM) PhD fellowship. We thank the following organizations for the highly valuable contribution of the COVID-BioToul biobank: the CRB TBR, the Clinical Research Center 1436, and the Delegation for clinical research and innovation of the Toulouse University Hospital. The authors acknowledge Celine Beronne and Flavie Moreau of the IPBS Institute Animal Facility Level 3 (ASB3) members for their help regarding the operating and technical procedures. The authors acknowledge BEI for SARS-CoV-2 material transfer, including SARS-CoV-2 variants, NSP5- and NSP5 C145A -expressing plasmids, and antibodies.
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/7/7
Y1 - 2022/7/7
N2 - Inflammation observed in SARS-CoV-2-infected patients suggests that inflammasomes, proinflammatory intracellular complexes, regulate various steps of infection. Lung epithelial cells express inflammasome-forming sensors and constitute the primary entry door of SARS-CoV-2. Here, we describe that the NLRP1 inflammasome detects SARS-CoV-2 infection in human lung epithelial cells. Specifically, human NLRP1 is cleaved at the Q333 site by multiple coronavirus 3CL proteases, which triggers inflammasome assembly and cell death and limits the production of infectious viral particles. Analysis of NLRP1-associated pathways unveils that 3CL proteases also inactivate the pyroptosis executioner Gasdermin D (GSDMD). Subsequently, caspase-3 and GSDME promote alternative cell pyroptosis. Finally, analysis of pyroptosis markers in plasma from COVID-19 patients with characterized severe pneumonia due to autoantibodies against, or inborn errors of, type I interferons (IFNs) highlights GSDME/caspase-3 as potential markers of disease severity. Overall, our findings identify NLRP1 as a sensor of SARS-CoV-2 infection in lung epithelia.
AB - Inflammation observed in SARS-CoV-2-infected patients suggests that inflammasomes, proinflammatory intracellular complexes, regulate various steps of infection. Lung epithelial cells express inflammasome-forming sensors and constitute the primary entry door of SARS-CoV-2. Here, we describe that the NLRP1 inflammasome detects SARS-CoV-2 infection in human lung epithelial cells. Specifically, human NLRP1 is cleaved at the Q333 site by multiple coronavirus 3CL proteases, which triggers inflammasome assembly and cell death and limits the production of infectious viral particles. Analysis of NLRP1-associated pathways unveils that 3CL proteases also inactivate the pyroptosis executioner Gasdermin D (GSDMD). Subsequently, caspase-3 and GSDME promote alternative cell pyroptosis. Finally, analysis of pyroptosis markers in plasma from COVID-19 patients with characterized severe pneumonia due to autoantibodies against, or inborn errors of, type I interferons (IFNs) highlights GSDME/caspase-3 as potential markers of disease severity. Overall, our findings identify NLRP1 as a sensor of SARS-CoV-2 infection in lung epithelia.
KW - 3CL proteases
KW - Gasdermins
KW - NLRP1 inflammasome
KW - SARS-CoV-2
KW - epithelial cells
KW - pyroptosis
UR - https://www.scopus.com/pages/publications/85130477866
U2 - 10.1016/j.molcel.2022.04.033
DO - 10.1016/j.molcel.2022.04.033
M3 - Article
C2 - 35594856
SN - 1097-2765
VL - 82
SP - 2385-2400.e9
JO - Molecular cell
JF - Molecular cell
IS - 13
ER -
SDG 3 Good Health and Well-being