BETACORONAVIRUSES OPTIMIZE REPLICATION BY BALANCING ANTAGONISM OF INNATE IMMUNE RESPONSES AND ER STRESS RESPONSES
type: CreativeWork
description: Betacoronaviruses have emerged as a major threat to human health in the 21st century, although our understanding of their interactions with human cells remains limited. To better understand the determinants of human betacoronavirus infection and to identify potential therapeutic strategies, we examined interactions with cellular pathways poised to detect and respond to viral invasion: double-stranded (ds)RNA – a viral replication intermediate - sensing innate immune pathways and endoplasmic reticulum (ER) stress pathways. Here, we compare infections of respiratory tract derived cell lines with three betacoronaviruses representing different viral subgenera and different disease outcomes in infected humans: HCoV-OC43, a common cold virus; MERS-CoV, which caused an epidemic of severe pneumonia in the Arabian Peninsula with a 36% case fatality rate; and SARS-CoV-2, the causative agent of the COVID-19 pandemic, which induces disease ranging from asymptomatic infection to severe respiratory disease. We have found that these viruses have evolved different ways to evade or subvert these responses. MERS-CoV and HCoV-OC43 efficiently antagonize dsRNA-induced innate immune responses, while SARS-CoV-2 is less efficient and induces a greater response during infection. However, SARS-CoV-2 antagonizes IRE1α functions within the ER, which limits the induction of interferon stimulated genes during infection. MERS-CoV and HCoV-OC43, conversely, did not antagonize IRE1α, perhaps due to their ability to antagonize interferon signaling itself. Lastly, we found that all viruses induce ER stress responses, including PERK activation and eIF2α phosphorylation, which promote translational attenuation during stress or viral infection. While MERS-CoV and HCoV-OC43 are sensitive to translational shutoff by the host, they take advantage of cellular feedback loops to promote eIF2α dephosphorylation. SARS-CoV-2 failed to behave similarly, and, through an unknown mechanism, appears capable of evadi…
abstract: Betacoronaviruses have emerged as a major threat to human health in the 21st century, although our understanding of their interactions with human cells remains limited. To better understand the determinants of human betacoronavirus infection and to identify potential therapeutic strategies, we examined interactions with cellular pathways poised to detect and respond to viral invasion: double-stranded (ds)RNA – a viral replication intermediate - sensing innate immune pathways and endoplasmic reticulum (ER) stress pathways. Here, we compare infections of respiratory tract derived cell lines with three betacoronaviruses representing different viral subgenera and different disease outcomes in infected humans: HCoV-OC43, a common cold virus; MERS-CoV, which caused an epidemic of severe pneumonia in the Arabian Peninsula with a 36% case fatality rate; and SARS-CoV-2, the causative agent of the COVID-19 pandemic, which induces disease ranging from asymptomatic infection to severe respiratory disease. We have found that these viruses have evolved different ways to evade or subvert these responses. MERS-CoV and HCoV-OC43 efficiently antagonize dsRNA-induced innate immune responses, while SARS-CoV-2 is less efficient and induces a greater response during infection. However, SARS-CoV-2 antagonizes IRE1α functions within the ER, which limits the induction of interferon stimulated genes during infection. MERS-CoV and HCoV-OC43, conversely, did not antagonize IRE1α, perhaps due to their ability to antagonize interferon signaling itself. Lastly, we found that all viruses induce ER stress responses, including PERK activation and eIF2α phosphorylation, which promote translational attenuation during stress or viral infection. While MERS-CoV and HCoV-OC43 are sensitive to translational shutoff by the host, they take advantage of cellular feedback loops to promote eIF2α dephosphorylation. SARS-CoV-2 failed to behave similarly, and, through an unknown mechanism, appears capable of evadi…
author: Renner, David, Michael
language: en
keywords: Life Sciences, Microbiology
date published: 2023
date modified: 2026-07-24T03:46:44Z
provider: University of Pennsylvania
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Pennsylvania