Improving our understanding of the events that cause anti-fungal allergic inflammation

Immune checkpoints that underpin fungal allergic airway disease

Dr Peter Cook

Dean’s Fellow

Dr Peter Cook

Tel: 0161 306 6052

Email: peter.c.cook@manchester.ac.uk

Our lungs are exposed to hundreds of fungal spores on a daily basis. For the majority of people, cells of the immune system clear these spores without any sign of disease. However, in some individuals the immune cells in the lung start to react to the inhaled spores that can trigger asthma and, in some cases, severe fungal allergic disease. One of the most common fungi, Aspergillus, is also one of the major types that causes this severe asthmatic disease. We do not understand how, or why, immune cells react to Aspergillus in these individuals, and the number of these cases is rising. Treatment with anti-fungal drugs that kill the fungi in the lung can be successful, but these drugs can have dangerous side effects. Additionally, there have been reports of fungal strains developing resistance to these drugs. Therefore, there is an urgent need to identify what causes the immune response to initiate these types of responses.

The focus of our work is to understand how specific cells in the immune system that are key for activating inflammation, called dendritic cells, start to respond to Aspergillus spores and then trigger the allergic disease symptoms observed in patients. Asthma is often characterised as a condition associated with type-2 inflammation, evident through recruitment of eosinophils, but recent evidence has shown that other immune cells that were thought to oppose these responses, such as type-17 inflammatory neutrophils, can also exacerbate allergic disease. How the balance between these inflammatory states impacts disease severity in patients with allergic responses to Aspergillus remains unknown. Dendritic Cells (DCs) are specialised innate immune cells that are vital initiators of both type-2 and type-17 anti-fungal inflammation, it is not known whether DCs sustain, or regulate, chronic allergic disease. Previously I have revealed new novel mechanism(s) by which DCs utilise type-2 inflammation, yet the processes that DCs utilise to initiate and regulate the type-2/type-17 allergic response balance to fungi is very poorly understood.

To tackle these key questions we are utilizing a range of approaches in mouse models and analysis of cells from human patients to determine the key role of DCs in mediating anti-Aspergillus allergic disease. In collaboration with scientists from the Manchester Fungal Infection Group (MFIG), we are focused on identifying the specific Aspergillus signals that induce DCs to drive allergic inflammation. Identification of the key DCs and the fungal signatures that they recognise will allow us to go on and determine the signals DCs emit to trigger anti-fungal allergic disease.

Overall, this research will improve our understanding of the events that cause anti-fungal allergic inflammation. This will allow us to develop new therapeutics designed to stop the immune response to react against the Aspergillus spores and so dampen and prevent anti-fungal allergic disease.

Selected publications:

Cook, P.C. and MacDonald A.S. Dendritic cells in lung immunopathology. Semin Immunopathol. 2016, 38(4): 449-460.

Cook, P.C., Owen, H., Deaton, A.M., Borger, J.G., Brown, S.L., Clouaire, T., Jones, G-R., Jones, L.H., Lundie, R.J., Marley, A.K., Morrison, V.L., Phythian-Adams, A.T., Wachter, E., Webb, L.M., Sutherland, T.E., Thomas, G.D., Grainger, J.R., Selfridge, J., McKenzie, A.N.J., Allen, J.E., Fagerholm, S.C., Maizels, R.M., Ivens, A., Bird, A., and MacDonald, A.S. A dominant role for the methyl-CpG-binding protein Mbd2 in controlling Th2 induction by dendritic cells. Nat. Commun. 2015, 6:6920.

Cook, P.C., Jones, L.H., Jenkins, S.J., Wynn, T.A., Allen, J.E., and MacDonald, A.S. Alternatively activated dendritic cells regulate CD4+ T cell polarization in vitro and in vivo. PNAS 2012, 109: 9977-9982.

Jenkins, S.J., Ruckerl, D., Cook, P.C., Jones, L.H., Finkelman, F.D., van Rooijen, N., MacDonald, A.S. and Allen, J.E. Local macrophage proliferation, rather than recruitment from the blood, is a signature of Th2 inflammation. Science. 2011, 332: 1284-1288.

Cook, P.C., Aynsley, S.A., Turner, J.D., Jenkins, G.R., Van Rooijen, N., Leeto, M., Brombacher, F., and Mountford, A.P. Multiple helminth infection of the skin causes lymphocyte hypo-responsiveness mediated by Th2 conditioning of dermal myeloid cells. PLoS Pathogens. 2011, 7(3):e1001323.

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