Investigating the innate immune barriers that constrain the transmission of coronaviruses

Davies, Emma Louise (2025) Investigating the innate immune barriers that constrain the transmission of coronaviruses. PhD thesis, University of Glasgow.

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Abstract

Since the turn of the century, the emergence of three highly pathogenic coronaviruses highlights the importance of understanding coronavirus-host interactions. If sufficient cellular factors are available for a virus to complete its life cycle, genome-encoded post-entry blocks to replication may determine whether virus replication is successful. One such barrier is the interferon response, a signalling pathway upregulating hundreds of interferon-stimulated genes (ISGs), many of which encode proteins with specific and potent antiviral activity. The presence and timing of a functional interferon response is important in controlling coronavirus infection. Thus, identifying ISGs with antiviral activity can provide insights into genetic risk factors associated with coronavirus disease severity and the barriers to coronavirus zoonosis. To identify ISGs that inhibit unmodified coronaviruses, I optimised an arrayed ISG expression screening protocol that utilises immunostaining of the dsRNA replication intermediate and quantification of virus infection by plate-based image cytometry. I screened the endemic coronavirus HCoV-OC43 against multiple ISG libraries encoded into lentiviral vectors, including three published species libraries (human, macaque, bovine) and two newly generated libraries (mouse, bat). This revealed ISGs with known and novel antiviral activity against coronaviruses, including 2’-5’-oligoadenylate synthetase 2 (OAS2). OAS proteins classically activate RNase L via the synthesis of 2’-5’-oligoadenylates, resulting in the degradation of cellular and viral RNA. Alternative splicing generates two OAS2 isoforms, p69 and p71, exhibiting differential antiviral activity. I show that the p69 isoform restricts HCoV-OC43,while the p71 isoform restricts the unrelated picornavirus Cardiovirus A (EMCV) via different mechanisms. The OAS gene family thus enhances antiviral breadth in the host genome by both gene duplication and alternative splicing. This research has provided insights into how coronaviruses interact with the innate immune system.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: Q Science > QR Microbiology > QR180 Immunology
Q Science > QR Microbiology > QR355 Virology
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
Supervisor's Name: Fletcher, Dr. Adam, Palmarini, Professor Massimo and Wilson, Professor Sam
Date of Award: 2025
Depositing User: Theses Team
Unique ID: glathesis:2025-85339
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 15 Jul 2025 08:25
Last Modified: 15 Jul 2025 08:25
URI: https://theses.gla.ac.uk/id/eprint/85339
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