The IRE1-xbp1 branch of the unfolded protein response underpins cytokine induction and viral replication in SARS-CoV-2 infection

Resumen

The endoplasmic reticulum (ER) is an intracellular organelle involved, among other functions, in the synthesis and secretion of proteins. These processes are tightly regulated to control the quality of protein secretion. However, excessive protein load can perturb ER homeostasis leading to accumulation of misfolded proteins resulting in the activation of the unfolded protein response (UPR). Viral infections including SARS CoV-2, as a positive single stranded RNA (ssRNA) virus, might cause ER stress because of the exploitation of the host machinery for viral replication. Endosomal Toll-like receptors (TLR)7 and TLR8 sense ssRNA associated SARS-CoV-2 virus. Recognition of ssRNA by its cognate receptors drives transcription and translation of pro-inflammatory genes, which after release into the systemic circulation, may team up with the UPR to ignite the cytokine storm (CS) or viral sepsis observed in the severe forms of the disease. Our approach aimed to understand the connection between SARS-CoV-2 infection and the UPR, focusing on the role of the transcription factor spliced XBP1 in viral replication and cytokine overproduction. The study encompasses: i) the analysis of nasopharyngeal swabs samples and bronchiolo-alveolar aspirates of patients undergoing mechanical ventilation due to severe pneumonia hospitalized at the Internal Care Unit (ICU), ii) experiments in monocyte derived dendritic cells (MDDCs) stimulated via TLR7/8, iii) studies in vivo infection with SARS-CoV-2, and iv) the impact of the UPR modulation during the replication cycle in human epithelial cells infected with different variants of concern (VOCs). Taken collectively, the study has disclosed that the IRE1-XBP1 branch of the UPR is a host-dependent factor involved in SARS CoV-2 pathogenesis.