Direct cell to cell spread of influenza A viruses

Weir, Daniel (2026) Direct cell to cell spread of influenza A viruses. PhD thesis, University of Glasgow.

Abstract

Influenza A viruses (IAVs) continue to cause widespread morbidity and mortality across the globe, driven by their evolutionary capacity to evade immune responses and adapt to spread between diverse hosts. Despite extensive surveillance of population-level transmission, the mechanisms governing IAV spread between individual cells within infected tissues remain incompletely understood. The intercellular spread of IAVs can either occur by the release of virus particles or by the transfer of viral genomes directly between cells (direct cell to cell spread). Infection by extracellular viruses is well-studied, but the importance and wider implications of direct cell to cell spread during IAV infection is unclear. To investigate this, I first established tissue culture models in which I could quantify the frequency of IAV direct cell to cell spread. I show that, even in the presence of drugs that completely inhibit extracellular virus spread, up to 40% of IAV infected cells are able to infect their neighbours, an effect that was consistent between IAV strains with different virion morphologies. Direct cell to cell spread of IAVs can occur by the induction of intercellular membrane connections known as tunnelling nanotube-like structures (TLSs), which are capable of trafficking the viral genome between cells. I show that TLSs are formed by IAV infected cells in vivo, and used in vitro models to ask how IAVs induce their formation. I found that TLS formation is not induced by cytokine signalling from infected to uninfected cells, but induction requires intracellular IAV replication. I therefore looked at the intracellular responses to infection and found that the ability of IAVs to drive TLS formation can be modulated by chemically inhibiting, or inducing apoptosis. I then found that inhibiting apoptosis, which prevents IAVs from inducing TLSs, lead to a significant reduction in the ability of IAVs to directly spread between distant cells. Interestingly, I found that direct cell to cell contacts allow uninfected cells to suppress apoptosis of neighbouring infected cells, with data revealing a potential role of uninfected cell mitochondrial transfer to infected cells. The results of this thesis, which suggest that IAVs efficiently perform direct cell to cell spread and control their ability to so through a regulation of host cell apoptosis, identifies a new way in which a virus can manipulate its host to evade antiviral immune responses, ensuring its continued spread even within the restrictive environment of the respiratory tract.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QR Microbiology > QR355 Virology
• Colleges/Schools: College of Medical Veterinary and Life Sciences
• Funder's Name: Medical Research Council (MRC)
• Supervisor's Name: Hutchinson, Professor Edward
• Date of Award: 2026
• Depositing User: Theses Team
• Unique ID: glathesis:2026-85718
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 27 Jan 2026 15:43
• Last Modified: 27 Jan 2026 16:07
• Thesis DOI: 10.5525/gla.thesis.85718
• URI: https://theses.gla.ac.uk/id/eprint/85718

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