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

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 respo...

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Detalles Bibliográficos
Autores: Fernández Rodríguez, José Javier, Marín, Arturo, Rosales, Romel, Penrice-Randal, Rebekah, Mlcochova, Petra, Álvarez, Yolanda, Villalón-Letelier, Fernando, Yildiz, Soner, Pérez, Enrique, Rathnasinghe, Raveen, Cupic, Anastasija, Kehrer, Thomas, Uccellini, Melissa B., Alonso, Sara, Martínez, Fernando, McGovern, Briana Lynn, Clark, Jordan J., Sharma, Parul, Bayón, Yolanda, Alonso, Andrés, Albrecht, Randy A., White, Kris M., Schotsaert, Michael, Miorin, Lisa, Stewart, James P., Hiscox, Julian A., Gupta, Ravindra K., Irigoyen, Nerea, García-Sastre, Adolfo, Crespo, Mariano Sánchez, Fernández, Nieves
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2024
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/361079
Acceso en línea:http://hdl.handle.net/10261/361079
https://api.elsevier.com/content/abstract/scopus_id/85191001404
Access Level:acceso abierto
Palabra clave:COVID-19
Cytokines
Fluvoxamine
Pneumonia
TLR
Transcription factors
Unfolded protein response
Variants of concern
Viral sepsis
Descripción
Sumario: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.

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