Publications
130 results found
Corzo-Leon DE, Armstrong-James D, Denning DW, 2015, Burden of serious fungal infections in Mexico, MYCOSES, Vol: 58, Pages: 34-44, ISSN: 0933-7407
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- Citations: 25
Tanaka RJ, Boon NJ, Vrcelj K, et al., 2015, In silico modeling of spore inhalation reveals fungal persistence following low dose exposure, Scientific Reports, Vol: 5, ISSN: 2045-2322
The human lung is constantly exposed to spores of the environmental mould Aspergillus fumigatus, a major opportunistic pathogen. The spectrum of resultant disease is the outcome of complex host-pathogen interactions, an integrated, quantitative understanding of which lies beyond the ethical and technical reach permitted by animal studies. Here we construct a mathematical model of spore inhalation and clearance by concerted actions of macrophages and neutrophils, and use it to derive a mechanistic understanding of pathogen clearance by the healthy, immunocompetent host. In particular, we investigated the impact of inoculum size upon outcomes of single-dose fungal exposure by simulated titrations of inoculation dose, from 106 to 102 spores. Simulated low-dose (102) spore exposure, an everyday occurrence for humans, revealed a counter-intuitive prediction of fungal persistence (>3 days). The model predictions were reflected in the short-term dynamics of experimental murine exposure to fungal spores, thereby highlighting the potential of mathematical modelling for studying relevant behaviours in experimental models of fungal disease. Our model suggests that infectious outcomes can be highly dependent upon short-term dynamics of fungal exposure, which may govern occurrence of cyclic or persistent subclinical fungal colonisation of the lung following low dose spore inhalation in non-neutropenic hosts.
Bidula S, Sexton DW, Abdolrasouli A, et al., 2015, The Serum Opsonin L-ficolin Is Detected in Lungs of Human Transplant Recipients Following Fungal Infections and Modulates Inflammation and Killing of <i>Aspergillus fumigatus</i>, JOURNAL OF INFECTIOUS DISEASES, Vol: 212, Pages: 234-246, ISSN: 0022-1899
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- Citations: 35
Abdolrasouli A, Rhodes J, Beale MA, et al., 2015, Genomic Context of Azole Resistance Mutations in Aspergillus fumigatus Determined Using Whole-Genome Sequencing (vol 6, e00536, 2015), MBIO, Vol: 6, ISSN: 2150-7511
Bidula S, Sexton DW, Yates M, et al., 2015, H-ficolin binds Aspergillus fumigatus leading to activation of the lectin complement pathway and modulation of lung epithelial immune responses., Immunology, Vol: 146, Pages: 281-291, ISSN: 1365-2567
Aspergillus fumigatus is an opportunistic fungal pathogen that typically infects the lungs of immunocompromised patients leading to a high mortality. H-ficolin, an innate immune opsonin, is produced by type II alveolar epithelial cells and could participate in lung defences against infections. Here, we utilised the human type II alveolar epithelial cell line, A549, to determine the involvement of H-ficolin in fungal defence. Additionally, we investigated the presence of H-ficolin in bronchoalveolar lavage fluid (BAL) from transplant patients during pneumonia. H-ficolin exhibited demonstrable binding to A. fumigatus conidia via L-fucose, D-mannose and N-acetylglucosamine residues in a calcium- and pH-dependent manner. Moreover, recognition led to lectin complement pathway activation and enhanced fungal association with A549 cells. Following recognition, H-ficolin opsonization manifested an increase in IL-8 production from A549 cells which involved activation of the intracellular signalling pathways MEK 1/2, p38 MAPK and JNK. Finally, H-ficolin concentrations were significantly higher in BAL of patients with lung infections compared to control subjects (n=16; p=0.00726). ROC curve analysis further highlighted the potential of H-ficolin as a diagnostic marker for lung infection (AUC=0.77; p<0.0001). Thus, H-ficolin participates in A. fumigatus defence via activation of the lectin complement pathway, enhanced fungal-host interactions and modulated immune responses. This article is protected by copyright. All rights reserved.
Shirkhani K, Teo I, Armstrong-James D, et al., 2015, Nebulised amphotericin B-polymethacrylic acid nanoparticle prophylaxis prevents invasive aspergillosis, NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE, Vol: 11, Pages: 1217-1226, ISSN: 1549-9634
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- Citations: 22
Abdolrasouli A, Rhodes J, Beale M, et al., 2015, Genomic context of Azole-resistance mutations in Aspergillus fumigatus using whole-genome sequencing, mBio, Vol: 6, ISSN: 2161-2129
A rapid and global emergence of azole resistance has been observed in the pathogenic fungus Aspergillus fumigatus over the past decade. The dominant resistance mechanism appears to be of environmental origin and involves mutations in the cyp51A gene, which encodes a protein targeted by triazole antifungal drugs. Whole-genome sequencing (WGS) was performed for high-resolution single-nucleotide polymorphism (SNP) analysis of 24 A. fumigatus isolates, including azole-resistant and susceptible clinical and environmental strains obtained from India, the Netherlands, and the United Kingdom, in order to assess the utility of WGS for characterizing the alleles causing resistance. WGS analysis confirmed that TR34/L98H (a mutation comprising a tandem repeat [TR] of 34 bases in the promoter of the cyp51A gene and a leucine-to-histidine change at codon 98) is the sole mechanism of azole resistance among the isolates tested in this panel of isolates. We used population genomic analysis and showed that A. fumigatus was panmictic, with as much genetic diversity found within a country as is found between continents. A striking exception to this was shown in India, where isolates are highly related despite being isolated from both clinical and environmental sources across >1,000 km; this broad occurrence suggests a recent selective sweep of a highly fit genotype that is associated with the TR34/L98H allele. We found that these sequenced isolates are all recombining, showing that azole-resistant alleles are segregating into diverse genetic backgrounds. Our analysis delineates the fundamental population genetic parameters that are needed to enable the use of genome-wide association studies to identify the contribution of SNP diversity to the generation and spread of azole resistance in this medically important fungus.
Bertuzzi M, Schrettl M, Alcazar-Fuoli L, et al., 2015, Correction: The pH-Responsive PacC Transcription Factor of Aspergillus fumigatus Governs Epithelial Entry and Tissue Invasion during Pulmonary Aspergillosis., PLoS Pathog, Vol: 11
Shah A, Abdolrasouli A, Soresi S, et al., 2015, The Utility of Novel Multi-Stage Testing for the Diagnosis of Pulmonary Aspergillosis in a Cohort of Lung Transplant Recipients, 35th Annual Meeting and Scientific Sessions of the International-Society-for-Heart-and-Lung-Transplantation, Publisher: ELSEVIER SCIENCE INC, Pages: S306-S306, ISSN: 1053-2498
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- Citations: 2
Herbst S, Shah A, Moya MM, et al., 2015, Phagocytosis-dependent activation of a TLR9-BTK-calcineurin-NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus, EMBO Molecular Medicine, Vol: 7, Pages: 240-258, ISSN: 1757-4676
Transplant recipients on calcineurin inhibitors are at high risk of invasive fungal infection. Understanding how calcineurin inhibitors impair fungal immunity is a key priority for defining risk of infection. Here, we show that the calcineurin inhibitor tacrolimus impairs clearance of the major mould pathogen Aspergillus fumigatus from the airway, by inhibiting macrophage inflammatory responses. This leads to defective early neutrophil recruitment and fungal clearance. We confirm these findings in zebrafish, showing an evolutionarily conserved role for calcineurin signalling in neutrophil recruitment during inflammation. We find that calcineurin–NFAT activation is phagocytosis dependent and collaborates with NF‐κB for TNF‐α production. For yeast zymosan particles, activation of macrophage calcineurin–NFAT occurs via the phagocytic Dectin‐1–spleen tyrosine kinase pathway, but for A. fumigatus, activation occurs via a phagosomal TLR9‐dependent and Bruton's tyrosine kinase‐dependent signalling pathway that is independent of MyD88. We confirm the collaboration between NFAT and NF‐κB for TNF‐α production in primary alveolar macrophages. These observations identify inhibition of a newly discovered macrophage TLR9–BTK–calcineurin–NFAT signalling pathway as a key immune defect that leads to organ transplant‐related invasive aspergillosis.
Painter KL, Strange E, Parkhill J, et al., 2015, Staphylococcus aureus adapts to oxidative stress by producing H2O2-resistant small colony variants via the SOS response, Infection and Immunity, ISSN: 1098-5522
Armstrong-James D, 2014, Immunity to pulmonary aspergillosis in solid organ transplantation, Publisher: WILEY-BLACKWELL, Pages: 35-35, ISSN: 0019-2805
Bertuzzi M, Schrettl M, Alcazar-Fuoli L, et al., 2014, The pH-Responsive PacC Transcription Factor of <i>Aspergillus fumigatus</i> Governs Epithelial Entry and Tissue Invasion during Pulmonary Aspergillosis, PLOS PATHOGENS, Vol: 10, ISSN: 1553-7366
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- Citations: 112
Brown GD, Meintjes G, Kolls JK, et al., 2014, AIDS-related mycoses: the way forward, TRENDS IN MICROBIOLOGY, Vol: 22, Pages: 107-109, ISSN: 0966-842X
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- Citations: 24
Armstrong-James D, Meintjes G, Brown GD, 2014, A neglected epidemic: fungal infections in HIV/AIDS, TRENDS IN MICROBIOLOGY, Vol: 22, Pages: 120-127, ISSN: 0966-842X
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- Citations: 221
Shah A, Herbst S, Kannambath S, et al., 2013, CALCINEURIN INHIBITORS IMPAIR THE HOST INNATE IMMUNE RESPONSE TO INVASIVE ASPERGILLOSIS LIKELY DUE TO A CALCINEURIN-DEPENDANT DEFECT IN FUNGAL KILLING IN ALVEOLAR MACROPHAGES, JOURNAL OF INFECTION, Vol: 67, Pages: 343-344, ISSN: 0163-4453
Herbst S, Shah A, Carby M, et al., 2013, A new and clinically relevant murine model of solid-organ transplant aspergillosis, DISEASE MODELS & MECHANISMS, Vol: 6, Pages: 643-651, ISSN: 1754-8403
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- Citations: 32
Armstrong-James D, Teo I, Herbst S, et al., 2012, Renal Allograft Recipients Fail to Increase Interferon-γ During Invasive Fungal Diseases, AMERICAN JOURNAL OF TRANSPLANTATION, Vol: 12, Pages: 3437-3440, ISSN: 1600-6135
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- Citations: 13
Armstrong-James D, Harrison TS, 2012, Immunotherapy for fungal infections, CURRENT OPINION IN MICROBIOLOGY, Vol: 15, Pages: 434-439, ISSN: 1369-5274
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- Citations: 23
Armstrong-James DPH, bignell E, 2012, Pathosystematic Studies and the Rational Design of Antifungal Interventions, Antimicrobial Drug Discovery: Emerging Strategies
Armstrong-James DPH, Dhesi Z, Herbst S, 2012, Transcript profiling of the murine immune response to invasive aspergillosis, Host-Fungus Interactions, Editors: brand, macallum, Publisher: Springer, Pages: 435-444
Dhesi Z, Herbst S, Armstrong-James D, 2012, Transcript profiling of the murine immune response to invasive aspergillosis., Methods Mol Biol, Vol: 845, Pages: 435-444
Invasive aspergillosis is an opportunistic infection for which complex host-pathogen interactions determine infection outcome. In particular, immunosuppressive therapies and other host factors, such as neutropenia, need to be taken into account when modelling the immune response to aspergillosis. Mammalian models have been developed in order to gain a deeper understanding of these biological interactions, which cannot be easily replicated in vitro. In vivo transcript profiling is emerging as a valuable technique to gain an overview of host responses to invasive infections. This approach can be applied to specific tissue sections, whole organs, or peripheral blood leukocyte populations. Here we describe a microarray technique for analyzing transcript profiles from whole lung homogenates in the context of invasive aspergillosis. This approach has the advantage of enabling a broad overview of the immune responses that govern disease outcome. The generic techniques described, however, have wider application to other infectious processes and tissue types.
Armstrong-James D, Copas AJ, Walzer PD, et al., 2011, A prognostic scoring tool for identification of patients at high and low risk of death from HIV-associated <i>Pneumocystis jirovecii</i> pneumonia, INTERNATIONAL JOURNAL OF STD & AIDS, Vol: 22, Pages: 628-634, ISSN: 0956-4624
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- Citations: 14
McGregor A, Wing JLK, Pollock E, et al., 2011, Management of quinolone-resistant typhoid osteomyelitis, BRITISH JOURNAL OF HOSPITAL MEDICINE, Vol: 72, Pages: 468-469, ISSN: 1750-8460
Armstrong-James D, Stebbing J, John L, et al., 2011, A trial of caspofungin salvage treatment in PCP pneumonia, THORAX, Vol: 66, Pages: 537-538, ISSN: 0040-6376
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- Citations: 39
Read P, Armstrong-James D, Tong CYW, et al., 2011, Missed opportunities for HIV testing-a costly oversight, QJM-AN INTERNATIONAL JOURNAL OF MEDICINE, Vol: 104, Pages: 421-424, ISSN: 1460-2725
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- Citations: 16
Flower B, Armstrong-James D, Dance C, et al., 2011, Blind, breathless, and paralysed from benign malaria, LANCET, Vol: 377, Pages: 438-438, ISSN: 0140-6736
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- Citations: 8
Armstrong-James D, Copas AJ, Walzer PD, et al., 2010, PREDICTING OUTCOME FROM HIV-ASSOCIATED PNEUMOCYSTIS PNEUMONIA, British-Thoracic-Society-Winter-Meeting 2010, Publisher: B M J PUBLISHING GROUP, Pages: A59-A59, ISSN: 0040-6376
Armstrong-James D, Teo IA, Shrivastava S, et al., 2010, Exogenous Interferon-γ Immunotherapy for Invasive Fungal Infections in Kidney Transplant Patients, AMERICAN JOURNAL OF TRANSPLANTATION, Vol: 10, Pages: 1796-1803, ISSN: 1600-6135
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- Citations: 71
Barrett NA, Armstrong-James D, Edgeworth J, et al., 2010, Novel H1N1 influenza and Panton-Valentine leukocidin <i>Staphylococcus aureus</i> necrotizing pneumonia, BRITISH JOURNAL OF HOSPITAL MEDICINE, Vol: 71, Pages: 350-351, ISSN: 1750-8460
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- Citations: 4
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