1 option
Betacoronaviruses Optimize Replication by Balancing Antagonism of Innate Immune Responses and ER Stress Responses / David Renner.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Renner, David, author.
- Language:
- English
- Subjects (All):
- Virology.
- Microbiology.
- Immunology.
- Cellular biology.
- Molecular biology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Local Subjects:
- Virology.
- Microbiology.
- Immunology.
- Cellular biology.
- Molecular biology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Physical Description:
- 1 online resource (220 pages)
- Distribution:
- Ann Arbor : ProQuest Dissertations & Theses, 2023
- Contained In:
- Dissertations Abstracts International 85-08B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.
- Language Note:
- English
- Summary:
- 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 HCoVOC43 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 new coronaviruses spilling into humans, research such as this is critical to identify new countermeasures for the next unknown threat.
- Notes:
- Source: Dissertations Abstracts International, Volume: 85-08, Section: B.
- Advisors: Weiss, Susan R.; Committee members: Weitzman, Matthew D.; Cherry, Sara; Beers, Michael F.; Jurado, Kellie Ann.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2023.
- Local Notes:
- School code: 0175
- ISBN:
- 9798381471656
- Access Restriction:
- Restricted for use by site license.
The Penn Libraries is committed to describing library materials using current, accurate, and responsible language. If you discover outdated or inaccurate language, please fill out this feedback form to report it and suggest alternative language.