The impact of influenza on the behaviour of lung basal cells

Shearer, Patrick Douglas Albert (2024) The impact of influenza on the behaviour of lung basal cells. PhD thesis, University of Glasgow.

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Influenza is the cause of 5 million infections globally, resulting in around 500,000 deaths each year. Despite targeted anti-viral drugs and vaccines, influenza viruses are poorly controlled and pose a particular threat to those who suffer chronic diseases. During infection, virus and immune-mediated damage destroys the airway structure needed for gas exchange and repairing this damage is essential for survival. Lung repair is driven by activation of progenitor cells, but how they carry out this repair is not well understood. Lung progenitors are difficult to study as they are a rare cell type in the lung, and the protocols for lung digest are not optimised for recovery of progenitors. We developed a new protocol for increasing the yield of progenitors from mouse lung tissue and used published transcriptomics data sets to identify progenitor cells in silico. We aimed to understand how the composition of the lung was changed during damage, so we infected mice with influenza A virus and studied how the behaviour of the epithelial progenitors changed. We found the composition of the lung changes during the peak and recovery phases of influenza. This change in composition correlates with increased activation and proliferation of progenitors and we show that this is accompanied by a change in cell metabolism, particularly an increase in glycolysis. We found that upper airway basal cells rely on IL-10 signalling to initiate this activation, and we suggest that the immunoregulatory response is necessary to initiate basal cell activation. We considered that lung basal cells might be changed by direct interaction with influenza viruses and using novel, fluorescent influenza A virus, we show that a subset of lung basal cells are directly infected by influenza virus but survive. Direct infection triggers an increase in stress, and further increases in glycolytic metabolism. We suggest this metabolic adaption of epithelial progenitors is a critical step in initiating lung repair after damage, and the stress seen in directly infected cells could result in improper dysplastic repair. Our data support the proposal that new treatments for respiratory diseases could consider targeting mechanisms of repair. Improving how the host repairs damage could not only be effective alongside drugs and vaccines in treating acute infections like influenza, but also in resolving chronic inflammatory such as COPD.

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
Supervisor's Name: Perona-Wright, Dr. Georgia
Date of Award: 2024
Depositing User: Theses Team
Unique ID: glathesis:2024-84417
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 01 Jul 2024 10:14
Last Modified: 01 Jul 2024 10:15
Thesis DOI: 10.5525/gla.thesis.84417
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