Respiratory virus coinfection and superinfection exclusion

Sims, Anna (2024) Respiratory virus coinfection and superinfection exclusion. PhD thesis, University of Glasgow.

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Influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are responsible for two of the deadliest pandemics in modern history, and the emergence of pandemic respiratory viruses remains constant threat to human life. The emergence of novel pandemic viruses is driven by genetic exchange between existing viruses during coinfection of cells. Coinfection of cells can be controlled by superinfection exclusion (SIE), a mechanism by which a previously infected cell becomes resistant to secondary viral infection after a period of time. SIE is known to be induced following IAV infection but its mechanism is unknown, while SIE has not yet been observed for any coronavirus, including SARS-CoV-2. In this thesis, I use isogenic reporter viruses to study SIE, defining the kinetics of onset for IAV and presenting the first evidence for SIE for SARS-CoV-2. I demonstrate that in both cases SIE onset does not occur immediately, but that infected cells shift from a permissive to exclusionary state within 6 hours of primary infection. I used this system to investigate the mechanism for IAV SIE, showing that it is unlikely to be driven by direct competition between the viruses, or by the cellular interferon response. I then modelled the foci of infection observed within infected hosts in vitro using plaque assays. For both viruses, I also show how SIE at the level of individual cells affects the ability of virus populations to coinfect cells during localised viral spread. I found that viruses within one plaque could coinfect freely, as all new infections were of cells that had not yet established SIE. In contrast, viruses spreading towards each other from separate plaques could only establish minimal regions of overlap before SIE blocked further coinfection. For IAV, these interactions were then also observed in the lungs of infected mice. The results suggests that the kinetics of SIE onset separate a spreading infection into discrete regions, within which interactions between virus populations can occur freely, and between which they are blocked. These findings are likely to apply other viruses that induce SIE. Finally, I investigated the potential for coinfection between IAV and SARS-CoV-2. I found no evidence of SIE, but instead found evidence of viral interference mediated by type-1 interferon. Understanding the mechanisms and dynamics of SIE could help us understand coinfection and the generation of novel pandemic viruses, and potentially aid in predicting when new pandemics will arise.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Subjects: 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: Hutchinson, Dr. Edward
Date of Award: 2024
Depositing User: Theses Team
Unique ID: glathesis:2024-84265
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 26 Apr 2024 09:27
Last Modified: 26 Apr 2024 11:28
Thesis DOI: 10.5525/gla.thesis.84265
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