McCabe, TM; (2016) The role of airway epithelia in anti-pathogen responses, innate immunity and lung repair. Doctoral thesis , UCL (University College London).

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Abstract

Airway epithelia are the first targets of influenza A virus (IAV) infection and the first cells to respond, contributing to immunity, pathology and recovery. The magnitude and quality of epithelial responses may depend on exacerbations like bacterial superinfections and be determined by the host genetic background. We therefore use a primary mouse tracheal epithelial cell (mTECs) cultures to identify epithelial determinants of susceptibility and protection. We assessed mTEC responses to IAV-bacterial co-exposure and found that the massive in vivo cytokine and chemokine response to co-infection is reflected in vitro by strongly increased epithelial responses to a combined viral-bacterial stimulus compared to single stimuli. The antiviral transcriptional responses dominate the overall response in vivo and in vitro. We also compared the epithelial response to IAV between high interferon producing, susceptible 129S8 mice, and IAV-resistant moderate interferon producers, C57BL/6 mice. We found that 129S8-derived mTECs do not produce more interferons in response to IAV but respond more strongly to interferons and IAV by induction of cytokines and interferon-stimulated genes. 129S8-derived epithelia also proliferate and differentiate less well than C57BL/6 mTECs, suggesting reduced repair potential. The initial epithelial cell-intrinsic antiviral response and control of IAV depends on type I and/or III interferons (IFNαβ or IFNλ). When IFNα and IFNλ influenza treatments were compared, IFNα stimulated both innate immune cells and mTECs, increasing immunopathology and mortality. IFNλ treatment only induced antiviral epithelial responses but not the immune-mediated pathology triggered by IFNα. Therefore, IFNλ treatment helps control IAV and protects without inducing immunopathology. During recovery, lung epithelial stem cells must proliferate and differentiate to repair infection-induced epithelial damage. We found that IFN impaired epithelial regeneration by reducing stem cell proliferation and differentiation, likely through IFN-induced blockade of epidermal growth factor signalling. Thus antiviral immune responses, if mistimed or excessive, may impede post-infection lung repair. Together, mTECs help identify determinants of susceptibility and protection.

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