Opportunistic Pulmonary Pathogens
The group is focussed on the pathogenesis of opportunistic respiratory infections in the immunocompromised host. In particular, we are interested in interactions between major bacterial and fungal pathogens that are able to establish chronic infection in the lung, such as Pseudomonas aeruginosa, atypical mycobacteria and the mould Aspergillus fumigatus. These infections typically occur in individuals who have defects in pulmonary host defence, such as cystic fibrosis, X-linked agammaglobulinaemia, chronic airway diseases and lung transplantation. The work of the group is closely linked to the chronic respiratory infection team at the Royal Brompton Hospital.
During an MRC Clinician Scientist Award, the group described a novel Toll-like receptor 9- Bruton’s tyrosine kinase-calcineurin-NFAT signalling pathway that is activated in macrophages during phagocytosis. Further studies demonstrated that this pathway controls downstream necroptotic macrophage cell death. Blockade of these innate calcineurin pathways during organ transplantation immunosuppression could therefore be a key factor in recurrent respiratory infections in these patients. Our studies in cystic fibrosis models indicate that excessive inflammatory responses during phagocytosis lead to over-activation of the calcineurin pathway and a subsequent skewing of macrophage responses to infection away from apoptosis and towards necroptosis.
We are now developing techniques for live imaging of infection in the murine lung. This innovative approach is enabling us to determine the roles of key innate effector cells during initiation and resolution of infection. Current projects are focussed on the impact of Pseudomonas aeruginosa and mycobacteria on innate pulmonary responses to fungi.
Key recent publications:
Ibrutinib blocks Btk-dependent NF-ĸB and NFAT responses in human macrophages during Aspergillus fumigatus phagocytosis. Bercusson A, Colley T, Shah A, Warris A, Armstrong-James D. Blood. 2018 Jul 18. pii: blood-2017-12-823393. doi: 10.1182/blood-2017-12-823393.
From phagocytosis to metaforosis: Calcineurin's deadly role in innate processing of fungi. Armstrong-James D, de Boer L, Bercusson A, Shah A. PLoS Pathog. 2018 Jan 4;14(1):e1006627. doi: 10.1371/journal.ppat.1006627.
Immunotherapeutic approaches to treatment of fungal diseases. Armstrong-James D, Brown GD, Netea MG, Zelante T, Gresnigt MS, van de Veerdonk FL, Levitz SM. Lancet Infect Dis. 2017 Dec;17(12):e393-e402. doi: 10.1016/S1473-3099(17)30442-5.
Calcineurin Orchestrates Lateral Transfer of Aspergillus fumigatus during Macrophage Cell Death. Shah A, Kannambath S, Herbst S, Rogers A, Soresi S, Carby M, Reed A, Mostowy S, Fisher MC, Shaunak S, Armstrong-James DP. Am J Respir Crit Care Med. 2016 Nov 1;194(9):1127-1139.
Robb Cramer, Geisel School of Medicine at Dartmouth, Fungal adaptation and the host, 2016
Leo Carlin, Beatson Institute, University of Glasgow, In vivo imaging of pulmonary infection, 2015
Jacques Meis, Canisius Wilhelmina Hospital, Department of Medical Microbiology and Infectious DiseasesNijmegenthe Netherlands, Clinical fungal diversity, 2015
Dr Adilia Warris, University of Aberdeen, Fungal infections in cystic fibrosis, 2015
Professor Matthew Fisher, Infectious Diseases EpidemiologyImperial College London, Fungal genomics and the host, 2013
Boris Lenhard, MRC Clinical Sciences Centre, Imperial College London, Regulation of transcriptional responses to Aspergillus fumigatus in dendritic cells, 2013
Serge Mostowy, MRC CMBI, Imperial College London, Zebrafish models of aspergillosis, 2011
Global emergence of triazole resistance in Aspergillus fumigatus, EMBO Aids Mycoses Workshop 2016, Cape Town, South Africa, 2016
From bench to bedside: understanding risk for fungal infection in lung transplantation., Invasive Mycoses in Haematological Malignancies Meeting, Wurzburg, Germany, 2015
Fungal Immunotherapy, Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, 2014
PCP and mortality: what do clinical studies tell us about pathogenesis?, Embo AIDS Mycology Meeting 2013 Cape Town South Africa, University of Cape Town South Africa, 2013
Systems Biology of Fungal pH Adaptation, International Society of Human and Animal Mycology Conference, Paris, France, 2006