(MRC CASE DTP) The stratification of fungal airway disease patients to facilitate better treatment outcomes.

This project has the potential to make a significant impact to the lives of patients suffering with debilitating fungal disease. In collaboration with our industrial partners, F2G Ltd, we will identify key drivers of fungal allergy and identify potential routes to therapeutic intervention.

The fungus Aspergillus fumigatus is a major pathogen of the human airways. Exposure to this fungus is a frequent cause of asthma, and can to severe fungal asthma disease which impacts 10 million people worldwide. Most strikingly of the 0.5 million related asthma deaths each year, 50% are fungal asthmatics. There is an urgent need to better understand disease pathogenesis to inform the development of improved therapeutics and precision targeting of these therapeutics, as current agents are ineffective and resistance is developing.

Dendritic cells (DCs) are highly specialised cells that upon exposure to fungi, potently activate immune responses that can lead to asthma. Despite the prevalence, little is known about how exposure of DCs to Aspergillus elicits allergic responses. This project will address the key question of how Aspergillus prompt DCs to activate and direct immune inflammation, and how this leads to allergic disease. Aspergillus can germinate and grow rapidly in the airways and in doing so releases a myriad of components (e.g. proteins, metabolites, proteases, carbohydrates) that come into contact with DCs. However, it is now known which of these signals cause DCs to drive inflammation that underpins allergic disease or how they are regulated. Central to the project will be utilising a unique Aspergillus mutant stain library, to determine the key fungal derived components that are required for DCs to orchestrate and sustain allergic inflammation in the airways. We will assess if patients suffering from allergic diseases are defective in their response to any of the fungal allergens identified here (using well characterised bio-banked samples) and we will attempt to identify common SNPs in the genomes of these patients.

Our preliminary data suggests that inhaled spores need to germinate to induce an allergic reaction. Our industrial partners, F2G Ltd, have developed a novel antifungal therapy that is currently undergoing phase 2 clinical trials. This compound inhibits a novel fungal target that is required for spore germination. We will investigate whether their compound is able to interfere with the establishment of allergic responses in our models of infection and identify patient groups (using our bio-banked samples) where such therapeutics would be effective.

http://research.bmh.manchester.ac.uk/mfig
http://www.mccir.manchester.ac.uk