Abstract
Following reovirus infection, cells activate stress responses that repress canonical translation as a mechanism to limit progeny virion production. Work by others suggests that these stress responses, which are part of the integrated stress response (ISR), may benefit rather than repress reovirus replication. Here, we report that compared to untreated cells, treating cells with sodium arsenite (SA) to activate the ISR prior to infection enhanced viral protein expression, percent infectivity, and viral titer. SA-mediated enhancement was not strain-specific, but was cell-type specific. While SA pre-treatment of cells offered the greatest enhancement, treatment within the first 4 h of infection increased the percent of cells infected. SA activates the heme-regulated eIF2α (HRI) kinase, which phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α) to induce stress granule (SG) formation. Heat shock (HS), another activator of HRI, also induced eIF2α phosphorylation and SGs in cells. However, HS had no effect on percent infectivity or viral yield but did enhance viral protein expression. These data suggest that SA pre-treatment perturbs the cell in a way that is beneficial for reovirus and that this enhancement is independent of SG induction. Understanding how to manipulate the cellular stress responses during infection to enhance replication could help to maximize the oncolytic potential of reovirus.
Highlights
Acute viral infection induces stress within infected cells
Previous reports have suggested that stress granule (SG) form following infection with reovirus, but reports are conflicting as to when SGs appear and when they disappear in infected cells [15,16]
SGs were absent in mock-infected cells and began appearing in wells infected with type 3 Dearing (T3D) around 2 h p.i
Summary
Acute viral infection induces stress within infected cells. The integrated stress response (ISR)is activated in many cells during viral infection [1,2,3]. Acute viral infection induces stress within infected cells. Is activated in many cells during viral infection [1,2,3]. The ISR facilitates cellular survival and a return to homeostasis, or initiates cell death signaling under conditions of severe stress or when the initiating stressor is maintained [4]. Four distinct stress kinases can be activated in response to stress. These kinases may have a number of substrates, they all phosphorylate the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2α) at serine position 51. When eIF2α is phosphorylated, the GTP-exchange factor, eIF2B is unable to exchange GDP for GTP on eIF2. As a consequence eIF2B becomes sequestered and its effective levels drop, preventing efficient formation of the eIF2.GTP.Met-tRNAi ternary complex and inhibiting translation initiation [4]
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