BETACORONAVIRUSES OPTIMIZE REPLICATION BY BALANCING ANTAGONISM OF INNATE IMMUNE RESPONSES AND ER STRESS RESPONSES

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Degree type
Doctor of Philosophy (PhD)
Graduate group
Cell and Molecular Biology
Discipline
Life Sciences
Microbiology
Subject
Coronaviruses
Endoplasmic Reticulum Stress
GADD34
Innate Immunity
IRE1
Unfolded Protein Response
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2023
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Author
Renner, David, Michael
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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 evading host translational shutoff. Overall, this work reveals new ways in which betacoronaviruses interact with their host and identifies host pathways that can potentially be therapeutically targeted to disrupt betacoronavirus infection. With the threat of newcoronaviruses spilling into humans, research such as this is critical to identify new countermeasures for the next unknown threat.

Advisor
Weiss, Susan, R
Date of degree
2023
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