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

  • Genes Immun. 2024 Feb;25(1):43-54. doi: 10.1038/s41435-023-00243-6.
José J Fernández  1 ,  Cristina Mancebo  1  2 ,  Sonsoles Garcinuño  3 ,  Gabriel March  3 ,  Yolanda Alvarez  1  2 ,  Sara Alonso  1 ,  Luis Inglada  4 ,  Jesús Blanco  5  6 ,  Antonio Orduña  3 ,  Olimpio Montero  1 ,  Tito A Sandoval  7  8  9 ,  Juan R Cubillos-Ruiz  7  8  9 ,  Elena Bustamante-Munguira  10 ,  Nieves Fernández  #  1  2 ,  Mariano Sánchez Crespo  #  11
Affiliations
  • 1. Unidad de Excelencia Instituto de Biomedicina y Genética Molecular, CSIC-Universidad de Valladolid, 47003, Valladolid, Spain.
  • 2. Departamento de Bioquímica, Biología Molecular y Fisiología, Universidad de Valladolid, 47003, Valladolid, Spain.
  • 3. Servicio de Microbiología, Hospital Clínico Universitario de Valladolid, Universidad de Valladolid, 47003, Valladolid, Spain.
  • 4. Servicio de Medicina Interna, Hospital Universitario Rio-Hortega, 47012, Valladolid, Spain.
  • 5. Servicio de Medicina Intensiva, Hospital Universitario Rio-Hortega, 47012, Valladolid, Spain.
  • 6. CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
  • 7. Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, 10065, USA.
  • 8. Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, 10065, USA.
  • 9. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA.
  • 10. Servicio de Medicina Intensiva, Hospital Clínico Universitario de Valladolid, 47003, Valladolid, Spain.
  • 11. Unidad de Excelencia Instituto de Biomedicina y Genética Molecular, CSIC-Universidad de Valladolid, 47003, Valladolid, Spain. [email protected].
  • # Contributed equally.
PMID: 38146001 DOI: 10.1038/s41435-023-00243-6
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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