Abstract
Despite being a major health problem, respiratory syncytial virus (RSV) infections remain without specific therapy. Identification of novel host cellular responses that play a role in the pathogenesis of RSV infection is needed for therapeutic development. The endoplasmic reticulum (ER) stress response is an evolutionarily conserved cellular signaling cascade that has been implicated in multiple biological phenomena, including the pathogenesis of some viral infections. In this study, we investigate the role of the ER stress response in RSV infection using an in vitro A549 cell culture model. We found that RSV infection induces a non-canonical ER stress response with preferential activation of the inositol-requiring enzyme 1 (IRE1) and activated transcription factor 6 (ATF6) pathways with no concomitant significant activation of the protein kinase R-like ER kinase (PERK) pathway. Furthermore, we discovered that IRE1 has an inhibitory effect on RSV replication. Our data characterize, for the first time, the nature of the ER stress response in the setting of RSV infection and identify the IRE1 stress pathway as a novel cellular anti-RSV defense mechanism.
Highlights
The endoplasmic reticulum (ER) stress response is increasingly implicated in the pathogenesis of viral infections
We found that Respiratory syncytial virus (RSV) infection induces a non-canonical ER stress response with preferential activation of the inositol-requiring enzyme 1 (IRE1) and activated transcription factor 6 (ATF6) pathways with no concomitant significant activation of the protein kinase R-like ER kinase (PERK) pathway
RSV Infection Induces ER Stress—To determine whether RSV infection leads to activation of the ER stress response, we infected A549 cells with RSV and measured the effect of the infection on expression of the downstream genes known to be transcriptionally activated during ER stress
Summary
The endoplasmic reticulum (ER) stress response is increasingly implicated in the pathogenesis of viral infections. We found that RSV infection induces a non-canonical ER stress response with preferential activation of the inositol-requiring enzyme 1 (IRE1) and activated transcription factor 6 (ATF6) pathways with no concomitant significant activation of the protein kinase R-like ER kinase (PERK) pathway. The upstream mediators are three ER-resident transmembrane proteins: activating transcription factor 6 (ATF6), protein kinase R-like ER kinase (PERK), and inositol-requiring enzyme 1 (IRE1). During ER stress, BiP is released from ATF6, PERK, and IRE1 because of competitive binding to the increasing levels of misfolded proteins in the ER lumen This allows the activation of the ER stress response [24]. We investigate the effects of RSV infection on the three arms of the ER stress response and describe a novel role for IRE1 activity as an inhibitor of RSV replication
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