Characterisation of a murine model of allergic aspergillosis for the identification of novel immunotherapeutic targets
File(s)
Author(s)
Williams, Thomas
Type
Thesis
Abstract
Frequent exposure to the ubiquitous fungus Aspergillus fumigatus gives rise to allergic bronchopulmonary aspergillosis (ABPA), an allergic disease that is estimated to affect over 4 million people worldwide and is characterised by pulmonary infiltrates, bronchiectasis, and loss of lung function. One predisposing factor for the development of ABPA is Cystic fibrosis (CF), a disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, characterised by persistent infections and increased inflammation in the lung. Approximately 30 to 65% of individuals with CF have A. fumigatus sensitisation, often leading to ABPA which results in increased inflammation in the CF lung contributing to lung damage and decline. Hence, it was aimed to investigate the hallmarks of inflammation during allergic aspergillosis to identify novel immunotherapeutic targets for the treatment of hyperinflammation in ABPA in regard to CF.
Here, using a repeat challenge model of infection, it is shown that allergic aspergillosis can be characterised by eosinophilia and neutrophilia of the airway accompanied by low level persistence of A. fumigatus. It is further shown that cell death occurs in the airways of this model, indicated by increased airway LDH levels, accompanied by hallmark inflammatory cytokines of the IL-1 superfamily, IL-1β and IL-33. These phenotypes are seen to be exaggerated in a murine model of CF with increased neutrophilia and IL-1β levels in the airway. Transcriptomic and proteomic analyses of bronchoalveolar lavage cells from mice with allergic aspergillosis further highlighted a role for the IL-1 superfamily in this model with increased levels of the ST2 and IL-1RAcP receptors as well as IL-1 family cytokines including IL-1β and IL-1α.
IL-1 superfamily member signalling through a number of pathways leads to the production of inflammatory components. A number of inhibitors for the prevention of IL-1 family member production, neutralisation of cytokines or blockade of receptors are available, some of which are already used in the clinic. Here it is shown that the blockade of caspase-11, using wedelolactone, results in the reduction of neutrophilia and IL-1β levels in the airway without an increase of fungal burden in the lung showing that upstream blockade of pathways related to IL-1 cytokines may be effective for the treatment of allergic inflammation.
Overall, these results highlight a role for the IL-1 superfamily in the inflammatory phenotype seen in allergic aspergillosis. It is shown that blockade of pathways related to the release and signalling of IL-1 cytokines may provide novel immunotherapeutic targets to reduce inflammation and lung damage during allergic aspergillosis, for which drugs already in use in the clinic can be repurposed.
Here, using a repeat challenge model of infection, it is shown that allergic aspergillosis can be characterised by eosinophilia and neutrophilia of the airway accompanied by low level persistence of A. fumigatus. It is further shown that cell death occurs in the airways of this model, indicated by increased airway LDH levels, accompanied by hallmark inflammatory cytokines of the IL-1 superfamily, IL-1β and IL-33. These phenotypes are seen to be exaggerated in a murine model of CF with increased neutrophilia and IL-1β levels in the airway. Transcriptomic and proteomic analyses of bronchoalveolar lavage cells from mice with allergic aspergillosis further highlighted a role for the IL-1 superfamily in this model with increased levels of the ST2 and IL-1RAcP receptors as well as IL-1 family cytokines including IL-1β and IL-1α.
IL-1 superfamily member signalling through a number of pathways leads to the production of inflammatory components. A number of inhibitors for the prevention of IL-1 family member production, neutralisation of cytokines or blockade of receptors are available, some of which are already used in the clinic. Here it is shown that the blockade of caspase-11, using wedelolactone, results in the reduction of neutrophilia and IL-1β levels in the airway without an increase of fungal burden in the lung showing that upstream blockade of pathways related to IL-1 cytokines may be effective for the treatment of allergic inflammation.
Overall, these results highlight a role for the IL-1 superfamily in the inflammatory phenotype seen in allergic aspergillosis. It is shown that blockade of pathways related to the release and signalling of IL-1 cytokines may provide novel immunotherapeutic targets to reduce inflammation and lung damage during allergic aspergillosis, for which drugs already in use in the clinic can be repurposed.
Version
Open Access
Date Issued
2023-06-20
Date Awarded
01/12/2023
License URL
Advisor
Armstrong-James, Darius
Shah, Anand
Sponsor
Cystic Fibrosis Trust
Grant Number
WHRR_PS3655
Publisher Department
Department of Infectious Disease
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)