My research is primarily focussed on improving outcome in pulmonary fungal lung disease (e.g. allergic bronchopulmonary aspergillosis, chronic pulmonary aspergillosis and within bronchiectasis/cystic fibrosis). In particular, my research focusses on two major areas; 1) Understanding host susceptibility to Aspergillus fumigatus; 2) Understanding evolution and acquisition of antifungal resistance in chronic lung disease. I collaborate closely with Dr Darius Armstrong-James,and Professor Matthew Fisher within the Department of Medicine at Imperial College London.
Host susceptibility to Aspergillus fumigatus
During a MRC funded clinical PhD research fellowship in the Armstrong-James laboratory at Imperial College, my research initially focussed on understanding the effects of calcineurin inhibition on the human alveolar macrophage response to Aspergillus fumigatus. I showed that calcineurin inhibition critically impairs the ability of alveolar macrophages to control fungal germination by altering downstream necroptotic pathways and macrophage 'metaforosis', a newly coined actin-dependent human macrophage transfer of conidia to neighbouring cells during programmed cell death, through calcineurin-dependent phosphorylation of the actin polymerase VASP.
Our research now focusses on how similar pathways are dysregulated within chronic lung disease such as Cystic Fibrosis leading to susceptibility to fungal infection using a combination of animal models and human in vitro experiments including induced pluripotent stem-cell-derived macrophage models of fungal infection.
I am a co-investigator in TrIFIC (Targeting immuotherapy for Fungal Infections in Cystic Fibrosis), a multi-centre Strategic Research Centre grant from the Cystic Fibrosis Trust aiming to combine cohort immunophenotyping with mechanistic investigation to identify targets for immunotherapeutic precison medicine to improve outcome in fungal disease.
We have recently shown a rapidly increased global spread of antifungal resistance, particularly affecting individuals with chronic pulmonary fungal disease. Within Cystic Fibrosis, approximately 20 percent of Aspergillus fumigatus isolates are resistance to first-line antifungal treatment with oral azole therapy. The evolution of reistance in this population is as yet unclear. The widespread use of azoles in agriculture is increasing environmental isolate resistance. Long-term azole therapy in these patients can also directly lead to resistance or place selective pressure to enable emergence of resistant infection. In collaboration with Professor Matthew Fisher and Dr Pantelis Geourgiou, Imperial College London, my research aims through a multi-centre research collaboration to validate novel diagnostics to rapidly detect resistance and use whole genome sequencing to better understand resistance evolution and acquisition.
Use of minimally supervised machine learning to analyse CT imaging in chronic pulmonary aspergillosis
Current interpretation of radiological imaging in chronic fungal infection is partiularly subjective and assessment of progression is difficult and often unreliable. I collaborate with Dr Elsa Angelini, BRC Imaging, Imperial College London to use minimally supervised machine learning to analyse and stratify CT images within chronic pulmonary aspergillosis. Further research is planned to use similar techniques across chronic suppurative lung infection.
Professor James Chalmers, University of Dundee, 2019
Professor Matthew Fisher, Imperial College London, 2019
Dr Elsa Angelini, Imperial College London, 2018
Dr Melody Zhifang Ni, Imperial College London, 2018
Dr Peter Kelleher, Imperial College London, 2017
Dr Lorenzo Picinali, Imperial College London, 2017
Dr Darius Armstrong-James, Imperial College London, 2012
Dr Pantelis Georgiou, Imperial College London