- Title
- The role and therapeutic targeting of novel host immune factors in viral infection-induced respiratory disease
- Creator
- Daly, Katie
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2025
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Influenza A viruses cause significant burden and pose an ongoing threat to global health due to their propensity to mutate rapidly, limiting the efficacy of preventative and therapeutic interventions. Novel therapeutic strategies that overcome these limitations are urgently needed to improve our preparedness for future endemic and pandemic outbreaks. Host innate immune responses are highly conserved, and appropriate induction of these significantly influence the outcome of infections. In at-risk populations, underlying dysregulation in innate immune responses drives susceptibility to infection and development of more severe disease. In this manuscript, we explore therapeutic modulation of host innate immune factors to identify novel treatment strategies for IAV infection and disease in healthy and susceptible populations. IFNε, HDAC6 and ASC have been identified, either in the literature or in preliminary investigations, to play novel and/or critical roles in shaping the innate immune response to IAV infection and impact the progression of IAV infection and associated disease. As such, the following investigations assess the function and therapeutic potential of targeting these factors in IAV infection. Chapter 1: This chapter presents the background to this thesis by summarising key considerations regarding IAV infections, viral mutation, and current therapies in addition to providing a detailed overview of the molecular mechanisms underpinning the innate immune response to IAV infection. This chapter outlines our current understanding of the role of innate immune responses in IAV infection and their role in viral defence and/or development of infection-induced disease in both healthy and susceptible populations. Crucially this chapter highlights gaps in our current knowledge surrounding the function of key innate factors, including IFNε, HDAC6 and ASC, in IAV infection. Chapter 2: This chapter provides information of the general experimental methods utilised for in vitro and in vivo investigations, which were employed consistently across chapters 3, 4 and 5. Specific methodologies unique to a singular investigation are detailed within the relevant chapters when necessary. Chapter 3: The studies outlined in this chapter utilise in vivo and ex vivo models of IAV infection to demonstrate that the novel, uniquely expressed type I IFN, IFNε, plays a detrimental role in the response to infection and may contribute to the susceptibility to infection seen in asthmatic populations. Specifically, I show that IFNε activity is associated with increased viral replication while IFNε deficiency or inhibition via αIFNε treatment protects against viral infection and reduces viral load. Importantly, I also demonstrate that IFNε responses are exaggerated in asthma, both at baseline and in response to infection, and this likely contributes to the underlying susceptibility to and severity of IAV infection experienced by this population. Furthermore, I have demonstrated that αIFNε protects against IAV infection in this susceptible population. Chapter 4: The studies outlined in this chapter elucidate the novel molecular mechanisms through which histone deacetylase (HDAC)6, an enzyme typically associated with epigenetic processes, promotes protective antiviral responses in IAV infection. A series of mechanistic in vitro studies in conjunction with in vivo models of HDAC6 supplementation in IAV infection were performed to investigate the role and interactions of HDAC6 in the immune response to IAV infection. We identify a novel HDAC6-regulated pathway which induces protective antiviral responses to IAV infection via the direct deacetylation of DDX1 protein. Furthermore, we show that modulation of this pathway via treatment with recombinant (r)HDAC6 protects against IAV infection in vivo and improves key features of disease, highlighting its potential as a novel therapeutic target. Chapter 5: The studies outlined in this chapter explore the role and therapeutic targeting of the inflammasome adaptor protein, ASC, in the innate response to IAV infection and development of infection-induced disease. ASC-mediated inflammasome responses have previously been identified as drivers of pathogenic inflammation in respiratory conditions, including in IAV induced-disease and asthma. Utilising the novel small molecule inhibitor of ASC function, AR23B, designed and synthesised by collaborators, we demonstrate the efficacy of targeting ASC in inhibiting the activation of NLRP3 and AIM2 inflammasomes in immune cells. Further, we show that AR23B treatment promotes the expression of antiviral factors while limiting the expression of proinflammatory factors and protects against IAV infection and disease in vivo in healthy and asthmatic populations. Moreover, AR23B proved effective in reducing inflammasome responses and lung function changes in experimental asthma, in the absence of infection. These studies identify novel roles for ASC in the response to IAV and suggest ASC inhibition may be an effective therapeutic strategy for both IAV infection and asthma. Chapter 6: This chapter discusses our findings in the general context of immune targeting therapies as a therapeutic strategy for the treatment of IAV infection. This chapter examines the benefits and potential risks associated with this general therapeutic strategy and outlines the future steps necessary to facilitate the translation of such interventions into clinically viable treatments.
- Subject
- influenza A Virus; innate immunity; host directed therapies; antiviral immunity; respiratory disease; inflammation
- Identifier
- http://hdl.handle.net/1959.13/1516945
- Identifier
- uon:57051
- Rights
- Copyright 2025 Katie Daly, This thesis is currently under embargo and will be available from 13.01.2026.
- Language
- eng
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