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Innate IRE1α-XBP1 activation by viral single-stranded RNA and its influence on lung cytokine production during SARS-CoV-2 pneumonia

Genes & Immunity volume 25, pages 43–54 (2024)Cite this article

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Abstract

The utilization of host-cell machinery during SARS-CoV-2 infection can overwhelm the protein-folding capacity of the endoplasmic reticulum and activate the unfolded protein response (UPR). The IRE1α-XBP1 arm of the UPR could also be activated by viral RNA via Toll-like receptors. Based on these premises, a study to gain insight into the pathogenesis of COVID-19 disease was conducted using nasopharyngeal exudates and bronchioloalveolar aspirates. The presence of the mRNA of spliced XBP1 and a high expression of cytokine mRNAs were observed during active infection. TLR8 mRNA showed an overwhelming expression in comparison with TLR7 mRNA in bronchioloalveolar aspirates of COVID-19 patients, thus suggesting the presence of monocytes and monocyte-derived dendritic cells (MDDCs). In vitro experiments in MDDCs activated with ssRNA40, a synthetic mimic of SARS-CoV-2 RNA, showed induction of XBP1 splicing and the expression of proinflammatory cytokines. These responses were blunted by the IRE1α inhibitor MKC8866, the TLR8 antagonist CU-CPT9a, and knockdown of TLR8 receptor. In contrast, the IRE1α-XBP1 activator IXA4 enhanced these responses. Based on these findings, the TLR8/IRE1α system seems to play a significant role in the induction of the proinflammatory cytokines associated with severe COVID-19 disease and might be a druggable target to control cytokine storm.

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Fig. 1: XBP1 mRNA transcripts in nasopharyngeal samples.
Fig. 2: Expression of the mRNA of different cytokines in BAAs of patients under mechanical ventilation.
Fig. 3: Association of sXBP1 and viral replication with cytokine expression in BAAs.
Fig. 4: Expression of genes involved in monocytic-lineage differentiation in BAAs.
Fig. 5: Effect of the IRE1α activator IXA4 on the expression of cytokines elicited by ssRNA40.
Fig. 6: TLR8 and the IRE1α-XBP1 arm in MDDCs.

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Data availability

The data are available from the corresponding author on reasonable request.

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Acknowledgements

Biobanco del Centro de Hemoterapia y Hemodonación de Castilla y León is thanked for providing buffy coats. Staff from the Intensive Care Unit of Hospital Clínico Universitario de Valladolid is thanked for the effort devoted to patient follow-up care and sample collection. BioRender.com software was used in some figures.

Funding

This work was supported by Junta de Castilla y León/Fondo Social Europeo. Valladolid Section of Asociación Española contra el Cáncer. Fondo COVID-19 del Instituto de Salud Carlos III/Junta de Castilla y León. European Commission-NextGenerationEU, (Regulation EU 2020/2094), through CSIC’s Global Health Platform (PTI Salud Global). Plan Nacional de Salud y Farmacia Grant SAF2017-83079-R and Grant PID2020-113751RB-I00 funded by MCIN/AEI/ 10.13039/501100011033. Junta de Castilla y León/Fondo Social Europeo Grants. CSI035P17 and VA175P20. Proyecto SEAHORSE INFRARED: IR2020-1-UVA05.

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Author notes

  1. These authors contributed equally: Nieves Fernández, Mariano Sánchez Crespo.

Authors and Affiliations

  1. Unidad de Excelencia Instituto de Biomedicina y Genética Molecular, CSIC-Universidad de Valladolid, 47003, Valladolid, Spain

    José J. Fernández, Cristina Mancebo, Yolanda Alvarez, Sara Alonso, Olimpio Montero, Nieves Fernández & Mariano Sánchez Crespo

  2. Departamento de Bioquímica, Biología Molecular y Fisiología, Universidad de Valladolid, 47003, Valladolid, Spain

    Cristina Mancebo, Yolanda Alvarez & Nieves Fernández

  3. Servicio de Microbiología, Hospital Clínico Universitario de Valladolid, Universidad de Valladolid, 47003, Valladolid, Spain

    Sonsoles Garcinuño, Gabriel March & Antonio Orduña

  4. Servicio de Medicina Interna, Hospital Universitario Rio-Hortega, 47012, Valladolid, Spain

    Luis Inglada

  5. Servicio de Medicina Intensiva, Hospital Universitario Rio-Hortega, 47012, Valladolid, Spain

    Jesús Blanco

  6. CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain

    Jesús Blanco

  7. Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, 10065, USA

    Tito A. Sandoval & Juan R. Cubillos-Ruiz

  8. Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, 10065, USA

    Tito A. Sandoval & Juan R. Cubillos-Ruiz

  9. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA

    Tito A. Sandoval & Juan R. Cubillos-Ruiz

  10. Servicio de Medicina Intensiva, Hospital Clínico Universitario de Valladolid, 47003, Valladolid, Spain

    Elena Bustamante-Munguira

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  1. José J. Fernández
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Contributions

JJF, CM, SG, GM, YA, SA, TA, and OM designed and performed experiments and interpreted data. CM and TAS carried out real-time metabolic analysis. YA performed flow cytometry assays. JJF and SA carried out ChIP assays. LI, JB, AO, OM, JRCR, EBM, NF, and MSC guided the overall project design and assisted in data interpretation and writing of the manuscript. All authors approved the content of the final version of the manuscript.

Corresponding author

Correspondence to Mariano Sánchez Crespo.

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Competing interests

JRCR holds patents on the use of IRE1α modulators for the treatment of disease and serves as scientific consultant for Immagene B.V., NextRNA Therapeutics, Inc., and Autoimmunity Biologic Solutions, Inc. All other authors declare no potential conflicts of interest.

Ethical approval

The clinical part of the study was approved by the Ethics Committee of Area de Salud Valladolid Este (ref. PI-GR-20-2011 COVID). For in vitro experiments, MDDCs were obtained from human mononuclear cells collected from pooled buffy coats of healthy donors provided by Centro de Hemoterapia y Hemodonación de Castilla y León Biobank. The study was approved by the Bioethical Committee of the Spanish Council of Research (CSIC) and the written informed consent of all healthy donors was obtained at Centro de Hemoterapia y Hemodonación de Castilla y León Biobank. The process is documented by the Biobank authority according to the specific Spanish regulations. The ethics committee approved this procedure before starting the study.

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Fernández, J.J., Mancebo, C., Garcinuño, S. et al. Innate IRE1α-XBP1 activation by viral single-stranded RNA and its influence on lung cytokine production during SARS-CoV-2 pneumonia. Genes Immun 25, 43–54 (2024). https://doi.org/10.1038/s41435-023-00243-6

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