Severe Acute Respiratory Syndrome Coronavirus Envelope Protein Regulates Cell Stress Response and Apoptosis

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.

Virulence factors in porcine coronaviruses and vaccine design

“…It has been proposed that PEDV E protein induces UPR response, which leads to an increase in NF-κB activation (Xu et al, 2013a). This information is in agreement with previously reported data for SARS-CoV E protein, which has an important role in pathogenesis (DeDiego et al, 2011; DeDiego et al, 2014). …”

“…ER stress is also interconnected with the innate immune response and other host-cell responses (Hetz, 2012). The infection with many CoVs induces ER stress, and a role of UPR in pathogenesis has been described (DeDiego et al, 2011). In the case of enteric porcine CoVs, the induction of the UPR response has been reported for PEDV, with a negative effect on viral replication (Wang et al, 2014b).…”

The replication of a mouse adapted SARS-CoV in a mouse cell line stably expressing the murine SARS-CoV receptor mACE2 efficiently induces the expression of proinflammatory cytokines

“…SARS-CoV infection in DBT-mACE2 cells induced high levels of CPE, probably due to apoptosis, as it has been observed in other SARS-CoV-infected cell lines, such as Vero (DeDiego et al, 2011; Ren et al, 2005; Yan et al, 2004). This virus-induced cytopathology provides an additional experimental advantage of DBT-mACE2 cell lines, as the infection outcomes are overt and are similar to what happens to the epithelial respiratory cells in SARS patients (Lang et al, 2003; Zhang et al, 2003).…”

Development of next-generation respiratory virus vaccines through targeted modifications to viral immunomodulatory genes

“…Despite its various functions, E is dispensable for virus replication [42,56–59]. A SARS-CoV vaccine containing an E deletion has been generated and is highly attenuated in hamsters exhibiting less detected viral antigen by lung histopathology and lower viral titers [50,51,56,60]. An entirely new direction in coronavirus vaccine design has focused on modifying the replication fidelity of the virus.…”