The IRE1α-XBP1 arm of the unfolded protein response is a host factor activated in SARS-CoV-2 infection.

Autor: Fernández JJ; Unidad de Excelencia Instituto de Biomedicina y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Marín A; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Rosales R; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Penrice-Randal R; Department of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK., Mlcochova P; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Department of Medicine, University of Cambridge, Cambridge, UK., Alvarez Y; Unidad de Excelencia Instituto de Biomedicina y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain; Departamento de Bioquímica, Biología Molecular y Fisiología, Universidad de Valladolid, 47003 Valladolid, Spain., Villalón-Letelier F; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Yildiz S; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Pérez E; Unidad de Excelencia Instituto de Biomedicina y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain; Departamento de Ciencias de la Salud, Universidad Europea Miguel de Cervantes (UEMC), 47012 Valladolid, Spain., Rathnasinghe R; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Cupic A; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Kehrer T; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Uccellini MB; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Alonso S; Unidad de Excelencia Instituto de Biomedicina y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain., Martínez F; Unidad de Excelencia Instituto de Biomedicina y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain., McGovern BL; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Clark JJ; Department of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK., Sharma P; Department of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK., Bayón Y; Unidad de Excelencia Instituto de Biomedicina y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain; Departamento de Bioquímica, Biología Molecular y Fisiología, Universidad de Valladolid, 47003 Valladolid, Spain., Alonso A; Unidad de Excelencia Instituto de Biomedicina y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain., Albrecht RA; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., White KM; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Schotsaert M; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Miorin L; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Stewart JP; Department of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK; Department of Infectious Diseases, University of Georgia, GA 30602, USA., Hiscox JA; Department of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK; Infectious Diseases Horizontal Technology Centre (ID HTC), A*STAR, Singapore, Singapore; Department of Preventive Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China., Gupta RK; Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Department of Medicine, University of Cambridge, Cambridge, UK., Irigoyen N; Division of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, UK., García-Sastre A; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: adolfo.garcia-sastre@mssm.edu., Crespo MS; Unidad de Excelencia Instituto de Biomedicina y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain. Electronic address: sanchezcrespomariano@gmail.com., Fernández N; Unidad de Excelencia Instituto de Biomedicina y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain; Departamento de Bioquímica, Biología Molecular y Fisiología, Universidad de Valladolid, 47003 Valladolid, Spain.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2024 Jun; Vol. 1870 (5), pp. 167193. Date of Electronic Publication: 2024 Apr 20.
DOI: 10.1016/j.bbadis.2024.167193
Abstrakt: SARS-CoV-2 infection can cause severe pneumonia, wherein exacerbated inflammation plays a major role. This is reminiscent of the process commonly termed cytokine storm, a condition dependent on a disproportionated production of cytokines. This state involves the activation of the innate immune response by viral patterns and coincides with the biosynthesis of the biomass required for viral replication, which may overwhelm the capacity of the endoplasmic reticulum and drive the unfolded protein response (UPR). The UPR is a signal transduction pathway composed of three branches that is initiated by a set of sensors: inositol-requiring protein 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6). These sensors control adaptive processes, including the transcriptional regulation of proinflammatory cytokines. Based on this background, the role of the UPR in SARS-CoV-2 replication and the ensuing inflammatory response was investigated using in vivo and in vitro models of infection. Mice and Syrian hamsters infected with SARS-CoV-2 showed a sole activation of the Ire1α-Xbp1 arm of the UPR associated with a robust production of proinflammatory cytokines. Human lung epithelial cells showed the dependence of viral replication on the expression of UPR-target proteins branching on the IRE1α-XBP1 arm and to a lower extent on the PERK route. Likewise, activation of the IRE1α-XBP1 branch by Spike (S) proteins from different variants of concern was a uniform finding. These results show that the IRE1α-XBP1 system enhances viral replication and cytokine expression and may represent a potential therapeutic target in SARS-CoV-2 severe pneumonia.
Competing Interests: Declaration of competing interest The A.G.S. laboratory has received research support from GSK, Pfizer, Senhwa Biosciences, Kenall Manufacturing, Blade Therapeutics, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, Applied Biological Laboratories and Merck, outside of the reported work. A.G.S. has consulting agreements for the following companies involving cash and/or stock: Castlevax, Amovir, Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Pharmamar, CureLab Oncology, CureLab Veterinary, Synairgen, Paratus and Pfizer, outside of the reported work. A.G.S. has been an invited speaker in meeting events organized by Seqirus, Janssen, Abbott and Astrazeneca. A.G.S is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York, outside of the reported work. A.M. is the creator of Omics Bioinformatics S.L. and owns all the stocks of this company. The M.S. laboratory has received unrelated research funding in sponsored research agreements from 7Hills Pharma, ArgenX N.V., Moderna and Phio Pharmaceuticals, which has no competing interest with this work. The article reflects the views of the authors and does not represent the views or policies of the FDA. All other authors declare that they have no conflict of interest.
(Copyright © 2024. Published by Elsevier B.V.)
Databáze: MEDLINE
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