Chelsea and Westminster Hospital, Department of Medicine: Infectious Diseases, Imperial College
The focus of my project is on inflammation in the airways of patients with cystic fibrosis (CF) caused by Aspergillus fumigatus, specifically looking at a group of signalling proteins called interferons. Interferons act as messengers in the immune system to turn on anti-fungal responses, such as inflammation, and have an important role in turning this response off when the job is done. This regulatory ability of interferons is particularly important because sustained immune responses can cause damage to the lungs and reduce lung function. To study this, I will be assessing the levels and functionality of interferons from patient samples and in a CF cell line that I will culture and challenge with Aspergillus conidia. This work will highlight if current interferon immunotherapies can be repurposed to treat Aspergillus fumigatus in patients with CF, without further damaging the lungs.
Imperial College London
My project is focused on macrophage cell death, induced by Aspergillus fumigatus, and the inflammation this leads to in the context of cystic fibrosis (CF). Macrophages are phagocytes and are vital in controlling infection by taking up pathogens and killing them, as well as by signalling to the rest of the immune system. However, pathogens such as Aspergillus fumigatus are able to induce inflammatory cell death which may promote fungal survival. Using experimental models of CF, I will assess which specific kinds of death are being induced in CF macrophages by Aspergillus fumigatus, such as necroptosis and pyroptosis, and what role this has in the increased inflammatory profile often seen in CF. Once the specific cell death types have been established, I will then assess if any cell death inhibiting drugs which are already available can be repurposed for this disease, allowing macrophages to survive and better deal with the fungal infection.
Imperial College London
My project focuses on identifying the differences in inflammatory response induced by Aspergillus fumigatus in people with cystic fibrosis (CF). Around a third of the people with CF infected with Aspergillus fumigatus goes on to develop Aspergillus bronchitis, a severe airway infection. While others experience allergic broncho-pulmonary aspergillosis, an airway allergy to Aspergillus fumigatus. Individuals who present with similar clinical conditions may have developed them from different pathways. To identify the people-to-people variation in disease development in the context of cystic fibrosis-associated pulmonary aspergillosis, I will be performing deep immuno-profiling on blood and sputum. Deep immuno-profiling allows for the identification for the presence or absence of biomarkers which can help to indicate the pathway/stage of disease progression for an individual. This work allows for the improvement in the treatment and diagnosis of cystic fibrosis-associated pulmonary aspergillosis as well as identify new targets for the development of novel immunotherapies.
MRC Centre for Medical Mycology, University of Exeter
My specific focus is on the inflammation induced by Aspergillus fumigatus in the airways of people with cystic fibrosis. A specific type of blood cell, the neutrophil, is mainly responsible for this inflammation and might have a harmful effect on the epithelial lining of the airways. To study this in greater detail, I will be using a tissue culture model to look at the migration of the neutrophils through the epithelial layer in response to being challenged by Aspergillus conidia. Once this has been established, I will be performing a variety of tests in order to determine the ability of immune cells, from both people with cystic fibrosis and healthy individuals, to kill the spores, as well as looking at the amount of damage caused to the epithelial cells. I will then asses if anti-inflammatory medications already available can be repurposed in order to prevent the damage to the epithelium, whilst allowing the immune system to fight of thfe fungus.
Imperial College London
My central question investigates the interaction of the Aspergillus proteome with microbial communities, immune cell subsets and pathways that drive T cell polarisation in lung inflammation. Aspergillus has a transcriptionally complex life-cycle and a detailed understanding of the interplay between different stages in fungal development, antigen-presenting cell polarisation, antigen recognition, T cell and NK cell subset polarisation will be essential to understand the optimal pathways to target for immune modulation to effectively down regulate the damaging inflammation while maintaining the host ability to fight infection and successfully clear the pathogen from CF lung.
Aberdeen Fungal Group, University of Aberdeen; MRC Centre for Medical Mycology, University of Exeter
My PhD project is focused on dampening excessive inflammation by cystic fibrosis phagocytes in response to Aspergillus fumigatus. It has been shown that CF phagocytes produce excessive reactive oxygen species upon Aspergillus challenge and this correlates with poorer lung function. We predict that this excessive inflammation is a key driver for lung function decline in CF patients. Therapies such as CFTR modulators improve lung function and reduce Aspergillus colonisation in CF however their effects on immune cell responses is largely unknown. My project is investigating the beneficial effect of CFTR modulators on phagocyte inflammatory responses to Aspergillus and the underpinning the molecular mechanisms.