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Defining the impact of Ibrutinib therapy and CFTR dysfunction on macrophage function in the innate immune response to Aspergillus fumigatus
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Bercusson-A-2020-PhD-Thesis.pdf | Thesis | 3.99 MB | Adobe PDF | View/Open |
Title: | Defining the impact of Ibrutinib therapy and CFTR dysfunction on macrophage function in the innate immune response to Aspergillus fumigatus |
Authors: | Bercusson, Amelia |
Item Type: | Thesis or dissertation |
Abstract: | Over recent years, the role of fungal pathogens within the respiratory microbiome has been increasingly recognised. Aspergillus fumigatus is the most commonly isolated organism and gives rise to a wide spectrum of disease, the nature of which depends on the outcome of the host-pathogen interaction. While the majority of people who inhale Aspergillus spores on a daily basis clear them without consequence, certain subgroups of the population appear to be pre-disposed to develop clinical disease. Patients with specific forms of immunocompromise are known to be susceptible to invasive infection but in others who develop Aspergillus lung disease, the nature of the immune dysfunction present is not clear. This PhD aimed to clarify the mechanisms of immune dysfunction that underlay two different clinical groups’ predisposition to Aspergillus lung disease, namely patients treated with Ibrutinib and patients with Cystic Fibrosis. I established that Ibrutinib inhibits the activation of signalling pathways crucial to normal macrophage function, thus compromising the innate immune response to Aspergillus fumigatus. Ibrutinib was also shown to suppress macrophage programmed necrotic cell death. Following on from this finding, I was able to demonstrate that necroptosis is a significant mode of programmed cell death in Aspergillus-infected macrophages and is regulated by signalling along a TLR9-BTK mediated pathway. The clinical phenotype of fungal disease in Cystic Fibrosis is different, being characterised by chronic infection and allergy. In an in-vitro model, I showed that dysfunctional signalling within CFTR-deficient macrophages gives rise to a hyper-inflammatory response to Aspergillus fumigatus characterised by increased cytokine release, excess macrophage cell death and impaired fungal killing. In an in-vivo model, this exaggerated inflammatory response was ineffective in clearing Aspergillus from the airways and gave rise to a phenotype of chronic neutrophilic inflammation consistent with CF clinical disease. |
Content Version: | Open Access |
Issue Date: | Jan-2019 |
Date Awarded: | Mar-2020 |
URI: | http://hdl.handle.net/10044/1/82028 |
DOI: | https://doi.org/10.25560/82028 |
Copyright Statement: | Creative Commons Attribution NonCommercial NoDerivatives Licence |
Supervisor: | Armstrong-James, Darius |
Sponsor/Funder: | Wellcome Trust (London, England) |
Funder's Grant Number: | 097377 |
Department: | Department of Infectious Disease |
Publisher: | Imperial College London |
Qualification Level: | Doctoral |
Qualification Name: | Doctor of Philosophy (PhD) |
Appears in Collections: | Department of Infectious Disease PhD Theses |
This item is licensed under a Creative Commons License