Severe acute respiratory syndrome coronavirus envelope protein regulates cell stress response and apoptosis

PLoS Pathog. 2011 Oct;7(10):e1002315. doi: 10.1371/journal.ppat.1002315. Epub 2011 Oct 20.

Abstract

Severe acute respiratory syndrome virus (SARS-CoV) that lacks the envelope (E) gene (rSARS-CoV-ΔE) is attenuated in vivo. To identify factors that contribute to rSARS-CoV-ΔE attenuation, gene expression in cells infected by SARS-CoV with or without E gene was compared. Twenty-five stress response genes were preferentially upregulated during infection in the absence of the E gene. In addition, genes involved in signal transduction, transcription, cell metabolism, immunoregulation, inflammation, apoptosis and cell cycle and differentiation were differentially regulated in cells infected with rSARS-CoV with or without the E gene. Administration of E protein in trans reduced the stress response in cells infected with rSARS-CoV-ΔE or with respiratory syncytial virus, or treated with drugs, such as tunicamycin and thapsigargin that elicit cell stress by different mechanisms. In addition, SARS-CoV E protein down-regulated the signaling pathway inositol-requiring enzyme 1 (IRE-1) of the unfolded protein response, but not the PKR-like ER kinase (PERK) or activating transcription factor 6 (ATF-6) pathways, and reduced cell apoptosis. Overall, the activation of the IRE-1 pathway was not able to restore cell homeostasis, and apoptosis was induced probably as a measure to protect the host by limiting virus production and dissemination. The expression of proinflammatory cytokines was reduced in rSARS-CoV-ΔE-infected cells compared to rSARS-CoV-infected cells, suggesting that the increase in stress responses and the reduction of inflammation in the absence of the E gene contributed to the attenuation of rSARS-CoV-ΔE.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology*
  • Cell Line, Tumor
  • Gene Deletion
  • Gene Expression Regulation, Viral*
  • Host-Pathogen Interactions
  • Humans
  • SARS Virus / genetics*
  • SARS Virus / pathogenicity
  • Severe Acute Respiratory Syndrome / metabolism
  • Severe Acute Respiratory Syndrome / pathology
  • Severe Acute Respiratory Syndrome / virology*
  • Stress, Physiological / drug effects
  • Stress, Physiological / genetics*
  • Viral Envelope Proteins / genetics*
  • Viral Envelope Proteins / metabolism
  • Virulence / genetics
  • Virus Replication

Substances

  • E protein, SARS coronavirus
  • Viral Envelope Proteins