Evidence map›Paper›PMID 38648902›Full record

ArticleBiochimica et biophysica acta. Molecular basis of disease2024

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

Jose Javier Fernández, Arturo Marín, Romel Rosales, Rebekah Penrice-Randal, Petra Mlcochova, Yolanda Alvarez, Fernando Villalón-Letelier, Soner Yildiz, Enrique Pérez, Raveen Rathnasinghe and 21 more

Open access · greenAbstract read
In one paragraph

Article in Biochimica et biophysica acta. Molecular basis of disease, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed
4.3field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

9 citing papers in PubMed, 11 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

31 authors at 5 institutions in 3 countries.

Jose Javier FernándezUnidad 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.
Arturo MarínDepartment 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.
Romel RosalesDepartment 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.
Rebekah Penrice-RandalDepartment of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.
Petra MlcochovaCambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Department of Medicine, University of Cambridge, Cambridge, UK.
Yolanda AlvarezUnidad 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.
Fernando Villalón-LetelierDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Soner YildizDepartment 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.
Enrique PérezUnidad 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.
Raveen RathnasingheDepartment 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.
Anastasija CupicDepartment 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.
Thomas KehrerDepartment 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.
Melissa B UccelliniDepartment 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.
Sara AlonsoUnidad de Excelencia Instituto de Biomedicina y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain.
Fernando MartínezUnidad de Excelencia Instituto de Biomedicina y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain.
Briana Lynn McGovernDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Jordan J ClarkDepartment of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.
Parul SharmaDepartment of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK.
Yolanda BayónUnidad 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.
Andrés AlonsoUnidad de Excelencia Instituto de Biomedicina y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain.
Randy A AlbrechtDepartment 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.
Kris M WhiteDepartment 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.
Michael SchotsaertDepartment 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.
Lisa MiorinDepartment 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.
James P StewartDepartment 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.
Julian A HiscoxDepartment 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.
Ravindra K GuptaCambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Department of Medicine, University of Cambridge, Cambridge, UK.
Nerea IrigoyenDivision of Virology, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, UK.
Adolfo García-SastreDepartment 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.
Mariano Sánchez CrespoUnidad de Excelencia Instituto de Biomedicina y Genética Molecular, CSIC-Universidad de Valladolid, 47003 Valladolid, Spain. Electronic address: sanchezcrespomariano@gmail.com.
Nieves FernándezUnidad 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.
Icahn School of Medicine at Mount Sinai · USUniversidad de Valladolid · ESInstituto de Biomedicina y Genética Molecular de Valladolid · ESUniversity of Cambridge · GBUniversity of Liverpool · GB

Funding

NIAID Centers of Excellence for Influenza Research and Response: Universal Influenza Vaccine Research Activities75N93021C00014 · NIAID · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI GARCIA-SASTRE, ADOLFO · 2021 to 2025
$62.6M
Conduits: Mount Sinai Health System Translational Science HubUL1TR004419 · NCATS · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Rosalind J Wright · 2022 to 2026
$46.4M
SARS-CoV adaptations through a Systems Biology Lens (SYBIL)U19AI135972 · NIAID · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Adolfo Garcia-Sastre · 2018 to 2026
$27.2M
Combined adjuvant approaches for enhancement of SARS-CoV-2 vaccine efficacyR01AI160706 · NIAID · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SCHOTSAERT, MICHAEL, WONG, PAMELA TINMOI · 2022 to 2025
$2.9M
COVID and Translational Science supercomputer (CATS)S10OD030463 · OD · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI KOVATCH, PATRICIA · 2021 to 2021
$2.0M
Big Omics Data Engine 2 SupercomputerS10OD026880 · OD · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI KOVATCH, PATRICIA · 2019 to 2019
$2.0M
Experimental and natural SARS-CoV-2 infection of the human pancreasR01DK130425 · NIDDK · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI HOMANN, DIRK, SCHOTSAERT, MICHAEL · 2021 to 2023
$1.3M
Adjuvant strategies for universal and multiseasonal influenza vaccine candidates in the context of pre-existing immunityR21AI176069 · NIAID · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI SCHOTSAERT, MICHAEL, WONG, PAMELA TINMOI · 2023 to 2024
$466k
The regulatory functions of mini viral RNAs in influenza virus infectionsR21AI147172 · NIAID · UNIVERSITY OF CAMBRIDGE · PI IRIGOYEN, NEREA · 2019 to 2020
$231k
Medical Research Council MR/W005611/1NCATS NIH HHS UL1 TR004419NIAID NIH HHS 75N93021C00014NIAID NIH HHS R01 AI160706NIAID NIH HHS R21 AI147172NIAID NIH HHS R21 AI176069NIAID NIH HHS U19 AI135972NIDDK NIH HHS R01 DK130425NIH HHS S10 OD026880NIH HHS S10 OD030463Wellcome Trust
6 · The paper itself

Abstract

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.

Indexed as

COVID-19EndoribonucleasesProtein Serine-Threonine KinasesSARS-CoV-2Unfolded Protein ResponseVirus ReplicationX-Box Binding Protein 1AnimalsCytokinesFemaleHumansMesocricetusMiceMice, Inbred C57BLSignal TransductionCytokinesEndoribonucleasesERN1 protein, humanErn1 protein, mouseProtein Serine-Threonine KinasesX-Box Binding Protein 1XBP1 protein, humanXbp1 protein, mouseCOVID-19CytokinesFluvoxaminePneumoniaTLRTranscription factorsUnfolded protein responseVariants of concernViral sepsis

Identifiers

PMID38648902
PMCPMC12191402
OpenAlexW4394989789

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.