Imperial College London

ProfessorSebastianJohnston

Faculty of MedicineNational Heart & Lung Institute

Asthma UK Clinical Chair
 
 
 
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Contact

 

+44 (0)20 7594 3764s.johnston

 
 
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Assistant

 

Mr Christophe Tytgat +44 (0)20 7594 3849

 
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Location

 

343Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
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549 results found

Singanayagam A, Glanville N, Cuthbertson L, Bartlett NW, Finney LJ, Turek E, Bakhsoliani E, Calderazzo MA, Trujillo-Torralbo M-B, Footitt J, James PL, Fenwick P, Kemp SV, Clarke TB, Wedzicha JA, Edwards MR, Moffatt M, Cookson WO, Mallia P, Johnston SLet al., 2019, Inhaled corticosteroid suppression of cathelicidin drives dysbiosis and bacterial infection in chronic obstructive pulmonary disease., Science Translational Medicine, Vol: 11, Pages: 1-13, ISSN: 1946-6234

Bacterial infection commonly complicates inflammatory airway diseases such as chronic obstructive pulmonary disease (COPD). The mechanisms of increased infection susceptibility and how use of the commonly prescribed therapy inhaled corticosteroids (ICS) accentuates pneumonia risk in COPD are poorly understood. Here, using analysis of samples from patients with COPD, we show that ICS use is associated with lung microbiota disruption leading to proliferation of streptococcal genera, an effect that could be recapitulated in ICS-treated mice. To study mechanisms underlying this effect, we used cellular and mouse models of streptococcal expansion with Streptococcus pneumoniae, an important pathogen in COPD, to demonstrate that ICS impairs pulmonary clearance of bacteria through suppression of the antimicrobial peptide cathelicidin. ICS impairment of pulmonary immunity was dependent on suppression of cathelicidin because ICS had no effect on bacterial loads in mice lacking cathelicidin (Camp-/-) and exogenous cathelicidin prevented ICS-mediated expansion of streptococci within the microbiota and improved bacterial clearance. Suppression of pulmonary immunity by ICS was mediated by augmentation of the protease cathepsin D. Collectively, these data suggest a central role for cathepsin D/cathelicidin in the suppression of antibacterial host defense by ICS in COPD. Therapeutic restoration of cathelicidin to boost antibacterial immunity and beneficially modulate the lung microbiota might be an effective strategy in COPD.

Journal article

Radzikowska U, Eljaszewicz A, Wawrzyniak P, Dreher A, Globinska A, Ruchti F, Tan G, Rodriguez-Coira J, Smolinska S, Gajdanowicz P, Pirozynski M, Kebadze T, Jackson DJ, Edwards M, Williamson RA, Moniuszko M, Jutel M, O' Mahony L, Johnston SL, Akdis CA, Sokolowska Met al., 2019, House dust mite priming enhances rhinovirus-induced inflammasome activation in asthma, Congress of the European-Academy-of-Allergy-and-Clinical-Immunology (EAACI), Publisher: WILEY, Pages: 5-5, ISSN: 0105-4538

Conference paper

Benedikz EK, Bailey D, Cook CNL, Goncalves-Carneiro D, Buckner MMC, Blair JMA, Wells TJ, Fletcher NF, Goodall M, Flores-Langarica A, Kingsley RA, Madsen J, Teeling J, Johnston SL, MacLennan CA, Balfe P, Henderson IR, Piddock LJV, Cunningham AF, McKeating JAet al., 2019, Bacterial flagellin promotes viral entry via an NF-kB and Toll Like Receptor 5 dependent pathway, SCIENTIFIC REPORTS, Vol: 9, ISSN: 2045-2322

Journal article

Narean JS, Glanville N, Nunn CM, Niespodziana K, Valenta R, Johnston SL, McLean GRet al., 2019, Epitope mapping of antibodies induced with a conserved rhinovirus protein generating protective anti-rhinovirus immunity, Vaccine, Vol: 37, Pages: 2805-2813, ISSN: 0264-410X

Human rhinovirus (RV) infections are the principle cause of common colds and precipitate asthma and chronic obstructive pulmonary disease (COPD) exacerbations. Currently there is no vaccine for RV which is largely due to the existence of ∼160 serotypes/strains. We demonstrated previously that immunising mice with highly conserved VP4 and VP2 regions of the RV polyprotein (RV-A16 VP0) generated cross-reactive immunity to RV in vivo. The current study investigated and mapped the epitopes of RV-A16 VP0 that are targets for antibodies in serum samples from VP0 immunisation and RV challenge studies in mice. Recombinant capsid proteins, peptide pools and individual peptides spanning the immunogen sequence (RV-A16 VP0) were assessed for IgG binding sites to identify epitopes. We found that peptide pools covering the C-terminus of VP4, the N-terminus of VP2 and the neutralising NIm-II site within VP2 were bound by serum IgG from immunised mice. The NIm-II site peptide pool blocked IgG binding to the immunogen RV-A16 VP0 and individual peptides within the pool binding IgG were further mapped. Thus, we have identified immunodominant epitopes of RV vaccine candidate RV-A16 VP0, noting that strong IgG binding antibodies were observed that target a key neutralising epitope that is highly variable amongst RV serotypes.

Journal article

Singanayagam A, Johnston SL, 2019, Not just the common cold: Rhinovirus infection in lung allograft recipients., Respirology

Journal article

Calderazzo MA, Trujillo-Torralbo M-B, Finney LJ, Singanayagam A, Bakhsoliani E, Padmanaban V, Kebadze T, Aniscenko J, Elkin SL, Johnston SL, Mallia Pet al., 2019, Inflammation and infections in unreported chronic obstructive pulmonary disease exacerbations, International Journal of Chronic Obstructive Pulmonary Disease, Vol: 2019, Pages: 823-832, ISSN: 1176-9106

Purpose: COPD patients often do not report acute exacerbations to healthcare providers – unreported exacerbations. It is not known whether variances in symptoms, airway obstruction, aetiology and inflammatory responses account for differences in reporting of COPD exacerbations. The aims of the study were to compare symptoms, lung function changes, aetiology and inflammatory markers between exacerbations that were reported to healthcare providers or treated, with those that were unreported and untreated.Patients and methods: We recruited a cohort of COPD patients and collected clinical data and blood and airway samples when stable and during acute exacerbations. Virological and bacterial analyses were carried out and inflammatory markers measured.Results: We found no differences in symptoms, lung function, incidence of infection and inflammatory markers between reported and unreported exacerbations. Subjects who reported all exacerbations had higher BODE scores, lower FEV1 and more exacerbations compared with those who did not.Conclusion: The failure to report exacerbations is not related to the severity, aetiology or inflammatory profile of the exacerbation. Patients with less severe COPD and less frequent exacerbations are less likely to report exacerbations. The decision to report an exacerbation is not an objective marker of exacerbation severity and therefore studies that do not count unreported exacerbations will underestimate the frequency of clinically significant exacerbations. A better understanding of the factors that determine non-reporting of exacerbations is required to improve exacerbation reporting.

Journal article

Potaczek DP, Unger SD, Zhang N, Taka S, Michel S, Akdag N, Lan F, Helfer M, Hudemann C, Eickmann M, Skevaki C, Megremis S, Sadewasser A, Alhamwe BA, Alhamdan F, Akdis M, Edwards MR, Johnston SL, Akdis CA, Becker S, Bachert C, Papadopoulos NG, Garn H, Renz Het al., 2019, Development and characterization of DNAzyme candidates demonstrating significant efficiency against human rhinoviruses, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 143, Pages: 1403-1415, ISSN: 0091-6749

Journal article

Lan F, Zhong H, Zhang N, Johnston SL, Wen W, Papadopoulos N, Zhang L, Bachert Cet al., 2019, IFN-lambda 1 enhances Staphylococcus aureus clearance in healthy nasal mucosa but not in nasal polyps, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 143, Pages: 1416-+, ISSN: 0091-6749

Journal article

Petrova NV, Emelyanova AG, Gorbunov EA, Edwards MR, Walton RP, Bartlett NW, Aniscenko J, Gogsadze L, Bakhsoliani E, Khaitov MR, Johnston SL, Tarasov SA, Epstein OIet al., 2019, Retraction notice to "Efficacy of novel antibody-based drugs against rhinovirus infection: In vitro and in vivo results" [Antiviral Research 142 (2017) 185-192]., Antiviral Res, Vol: 164, Pages: 176-176

Journal article

Bousquet J, Hellings PW, Agache I, Amat F, Annesi-Maesano I, Ansotegui IJ, Anto JM, Bachert C, Bateman ED, Bedbrook A, Bennoor K, Bewick M, Bindslev-Jensen C, Bosnic-Anticevich S, Bosse I, Brozek J, Brussino L, Canonica GW, Cardona V, Casale T, Sarabia AMC, Chavannes NH, Cecchi L, de Sousa JC, Costa E, Cruz AA, Czarlewski W, De Carlo G, De Feo G, Demoly P, Devillier P, Dykewicz MS, El-Gamal Y, Eller EE, Fonseca JA, Fontaine J-F, Fokkens WJ, Guzman M-A, Haahtela T, Illario M, Ivancevich J-C, Just J, Kaidashev I, Khaitov M, Kalayci O, Keil T, Klimek L, Kowalski ML, Kuna P, Kvedariene V, Larenas-Linnemann D, Laune D, Le LTT, Carlsen KL, Lourenco O, Mahboub B, Mair A, Menditto E, Milenkovic B, Morais-Almeida M, Mosges R, Mullol J, Murray R, Naclerio R, Namazova-Baranova L, Novellino E, O'Hehir RE, Ohta K, Okamoto Y, Okubo K, Onorato GL, Palkonen S, Panzner P, Papadopoulos NG, Park H-S, Paulino E, Pawankar R, Pfaar O, Plavec D, Popov TA, Potter P, Prokopakis EP, Rottem M, Ryan D, Salimaki J, Samolinski B, Sanchez-Borges M, Schunemann HJ, Sheikh A, Sisul J-C, Rajabian-Soderlund R, Sooronbaev T, Stellato C, To T, Todo-Bom A-M, Tomazic P-V, Toppila-Salmi S, Valero A, Valiulis A, Valovirta E, Ventura M-T, Wagenmann M, Wang DY, Wallace D, Waserman S, Wickman M, Yorgancioglu A, Zhang L, Zhong N, Zidarn M, Zuberbier T, Bousquet J, Hellings PW, Aberer W, Agache I, Akdis CA, Akdis M, Alberti MR, Almeida R, Amat F, Angles R, Annesi-Maesano I, Ansotegui IJ, Anto JM, Arnavielle S, Asayag E, Asarnoj A, Arshad H, Avolio F, Bacci E, Bachert C, Baiardini I, Barbara C, Barbagallo M, Baroni I, Barreto BA, Basagana X, Bateman ED, Bedolla-Barajas M, Bedbrook A, Bewick M, Beghe B, Bel EH, Bergmann KC, Bennoor KS, Benson M, Bertorello L, Biaoszewski AZ, Bieber T, Bialek S, Bindslev-Jensen C, Bjermer L, Blain H, Blasi F, Blua A, Marciniak MB, Bogus-Buczynska I, Boner AL, Bonini M, Bonini S, Bosnic-Anticevich CS, Bosse I, Bouchard J, Boulet LP, Bourret R, Bousquet PJ, Braido F, Briedis V, Brighet al., 2019, Allergic Rhinitis and its Impact on Asthma (ARIA) Phase 4 (2018): Change management in allergic rhinitis and asthma multimorbidity using mobile technology, Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 864-879, ISSN: 0091-6749

Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline by using the best approach to integrated care pathways using mobile technology in patients with allergic rhinitis (AR) and asthma multimorbidity. The proposed next phase of ARIA is change management, with the aim of providing an active and healthy life to patients with rhinitis and to those with asthma multimorbidity across the lifecycle irrespective of their sex or socioeconomic status to reduce health and social inequities incurred by the disease. ARIA has followed the 8-step model of Kotter to assess and implement the effect of rhinitis on asthma multimorbidity and to propose multimorbid guidelines. A second change management strategy is proposed by ARIA Phase 4 to increase self-medication and shared decision making in rhinitis and asthma multimorbidity. An innovation of ARIA has been the development and validation of information technology evidence-based tools (Mobile Airways Sentinel Network [MASK]) that can inform patient decisions on the basis of a self-care plan proposed by the health care professional.

Journal article

Greiller CL, Suri R, Jolliffe DA, Kebadze T, Hirsman AG, Griffiths CJ, Johnston SL, Martineau ARet al., 2019, Vitamin D attenuates rhinovirus-induced expression of intercellular adhesion molecule-1 (ICAM-1) and platelet-activating factor receptor (PAFR) in respiratory epithelial cells, Journal of Steroid Biochemistry and Molecular Biology, Vol: 187, Pages: 152-159, ISSN: 0960-0760

Human rhinoviruses commonly cause upper respiratory infections, which may be complicated by secondary bacterial infection. Vitamin D replacement reduces risk of acute respiratory infections in vitamin D-deficient individuals, but the mechanisms by which such protection is mediated are incompletely understood. We therefore conducted experiments to characterise the influence of the major circulating metabolite 25-hydroxyvitamin D (25[OH]D) and the active metabolite 1,25-dihydroxyvitamin D (1,25[OH]2D) on responses of a respiratory epithelial cell line (A549 cells) to infection with a major group human rhinovirus (RV-16). Pre-treatment of A549 respiratory epithelial cells with a physiological concentration (10-7M) of 25(OH)D induced transient resistance to infection with RV-16 and attenuated RV-16-induced expression of the genes encoding intercellular adhesion molecule 1 (ICAM-1, a cell surface glycoprotein that acts as the cellular receptor for major group rhinoviruses) and platelet-activating factor receptor (PAFR, a G-protein coupled receptor implicated in adhesion of Streptococcus pneumoniae to respiratory epithelial cells). These effects were associated with enhanced expression of the genes encoding the NF-κB inhibitor IκBα and the antimicrobial peptide cathelicidin LL-37. Our findings suggest possible mechanisms by which vitamin D may enhance resistance to rhinovirus infection and reduce risk of secondary bacterial infection in vitamin D-deficient individuals.

Journal article

Dunning J, Blankley S, Hoang LT, Cox M, Graham CM, James PL, Bloom CI, Chaussabel D, Banchereau J, Brett SJ, MOSAIC Investigators, Moffatt MF, O'Garra A, Openshaw PJMet al., 2019, Author Correction: Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza., Nature Immunology, Vol: 20, Pages: 373-373, ISSN: 1529-2908

In the version of this article initially published, a source of funding was not included in the Acknowledgements section. That section should include the following: P.J.M.O. was supported by EU FP7 PREPARE project 602525. The error has been corrected in the HTML and PDF version of the article.

Journal article

Potaczek DP, Unger SD, Zhang N, Taka S, Michel S, Akdag N, Lan F, Helfer M, Hudemann C, Eickmann M, Skevaki C, Megremis S, Sadewasser A, Alhamwe BA, Alhamdan F, Akdis M, Edwards M, Johnston SL, Akdis CA, Becker S, Bachert C, Papadopoulos NG, Garn H, Renz HEet al., 2019, Development of antirhinoviral DNAzymes for effective prevention of asthma exacerbations, Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI), Publisher: MOSBY-ELSEVIER, Pages: AB99-AB99, ISSN: 0091-6749

Conference paper

Zhu J, Message SD, Mallia P, Kebadze T, Contoli M, Ward CK, Barnathan ES, Mascelli MA, Kon OM, Papi A, Stanciu LA, Edwards MR, Jeffery PK, Johnston SLet al., 2019, Bronchial mucosal Interferon-α/β and pattern recognition receptor expression in experimental rhinovirus-induced asthma exacerbations, Journal of Allergy and Clinical Immunology, Vol: 143, Pages: 114-125.e4, ISSN: 0091-6749

BACKGROUND: The innate immune system senses viral infection via pattern recognition receptors (PRRs) leading to type I interferon (IFN) production: their roles in rhinovirus (RV)-induced asthma exacerbations in vivo are uncertain. OBJECTIVES: To compare bronchial mucosal type I IFN and PRR expression at baseline and following RV infection in atopic asthmatic and control subjects. METHODS: Immunohistochemistry was used to detect expression of IFN-α, IFN-β and the PRRs, toll-like receptor (TLR)-3, melanoma-differentiation-associated gene-5 (MDA-5) and retinoic-acid-inducible protein-I (RIG-I) in bronchial biopsies from 10 atopic asthmatics and 15 non-asthmatic non-atopic controls at baseline and on day four and six weeks following RV infection. RESULTS: We observed IFN-α/β deficiency in bronchial epithelium at three time points in asthma in vivo. Lower epithelial IFN-α/β expression was related to greater virus load, worse airway symptoms, airway hyperresponsiveness (AHR) and reductions in lung function during RV infection. We found lower frequencies of bronchial subepithelial monocytes/macrophages expressing IFN-α/β in asthma during infection. IFN deficiency at baseline was not accompanied by deficient PRR expression in asthma. Both epithelial and subepithelial PRR expression was induced during RV infection. RV infection increased numbers of subepithelial IFN/PRRs-expressing inflammatory cells were related to greater virus load, AHR and reductions in lung function. CONCLUSIONS: Bronchial epithelial IFN-α/β expression and numbers of subepithelial IFN-α/β-expressing monocytes/macrophages during infection were both deficient in asthma. Lower epithelial IFN-α/β expression was associated with adverse clinical outcomes following RV infection in vivo. Increases in subepithelial cells expressing IFN/PRRs during infection were also related to greater virus load/illness severity.

Journal article

O'Sullivan MJ, Mitchel J, Bochkov YA, Tan L, Kebadze T, Johnston SL, Gern JE, Park JAet al., 2019, Human Rhinovirus Infection Induces the Expression and Secretion of Endothelin-1, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Potaczek DP, Unger SD, Zhang N, Taka S, Michel S, Akdag N, Lan F, Helfer M, Hudemann C, Eickmann M, Skevaki C, Megremis S, Sadewasser A, Alhamwe BA, Alhamdan F, Akdis M, Edwards MR, Johnston SL, Akdis CA, Becker S, Bachert C, Papadopoulos NG, Garn H, Renz Het al., 2019, Development and Characterization of Antisense Oligonucleotides Against Human Rhinovirus for Efficient Prevention of Asthma Exacerbation, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Fischer M, Kirkman-Thomas A, Mallia P, Johnston SL, Johnson Set al., 2019, Elastase Activity as an Indicator of Exacerbation and Disease Severity in COPD, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Wiseman DJ, Kamal F, Finney L, Ritchie AI, Gent J, Edwards MR, Johnston SL, Donaldson GC, Openshaw PJ, Wedzicha JAet al., 2019, Respiratory Syncytial Virus (RSV) Detection Is Associated with an Increased Inflammatory Response in Stable (non-Exacerbating) Chronic Obstructive Pulmonary Disease (COPD) Patients, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Finney L, Fenwick PS, Kemp S, Bakhsoliani E, Belchamber KBR, Edwards MR, Donaldson GC, Donnelly L, Mallia P, Johnston SL, Wedzicha JAet al., 2019, Interferon Response to Human Rhinovirus Is Impaired in Alveolar Macrophages but Not Bronchial Epithelial Cells in Chronic Obstructive Pulmonary Disease, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Menditto E, Costa E, Midão L, Bosnic-Anticevich S, Novellino E, Bialek S, Briedis V, Mair A, Rajabian-Soderlund R, Arnavielhe S, Bedbrook A, Czarlewski W, Annesi-Maesano I, Anto JM, Devillier P, De Vries G, Keil T, Sheikh A, Orlando V, Larenas-Linnemann D, Cecchi L, De Feo G, Illario M, Stellato C, Fonseca J, Malva J, Morais-Almeida M, Pereira AM, Todo-Bom A, Kvedariene V, Valiulis A, Bergmann KC, Klimek L, Mösges R, Pfaar O, Zuberbier T, Cardona V, Mullol J, Papadopoulos NG, Prokopakis EP, Bewick M, Ryan D, Roller-Wirnsberger RE, Tomazic PV, Cruz AA, Kuna P, Samolinski B, Fokkens WJ, Reitsma S, Bosse I, Fontaine JF, Laune D, Haahtela T, Toppila-Salmi S, Bachert C, Hellings PW, Melén E, Wickman M, Bindslev-Jensen C, Eller E, O'Hehir RE, Cingi C, Gemicioğlu B, Kalayci O, Ivancevich JC, Bousquet J, MASK groupet al., 2018, Adherence to treatment in allergic rhinitis using mobile technology. the mask study, Clinical and Experimental Allergy, ISSN: 0954-7894

BACKGROUND: Mobile technology may help to better understand the adherence to treatment MASK-rhinitis (Mobile Airways Sentinel NetworK for allergic rhinitis) is a patient-centered ICT system. A mobile phone app (the Allergy Diary) central to MASK is available in 22 countries. OBJECTIVES: To assess the adherence to treatment in allergic rhinitis patients using the Allergy Diary App. METHODS: An observational cross-sectional study was carried out on all users who filled in the Allergy Diary from January 1, 2016 to August 1, 2017. Secondary adherence was assessed by using the modified Medication Possession Ratio (MPR) and the Proportion of days covered (PDC) approach. RESULTS: 12,143 users were registered. 6,949 users reported at least one VAS data recording. Among them, 1,887 users reported ≥ 7 VAS data. 1,195 subjects were included in the analysis of adherence. 136 (11.28%) users were adherent (MPR ≥70% and PDC ≤ 1.25), 51 (4.23%) were partly adherent (MPR ≥70% and PDC =1.50) and 176 (14.60%) were switchers. On the other hand, 832 (69.05%) users were non-adherent to medications (MPR<70%). Of those, the largest group was non-adherent to medications and the time interval was increased in 442 (36.68%) users. CONCLUSION AND CLINICAL RELEVANCE: Adherence to treatment is low. The relative efficacy of continuous versus on-demand treatment for AR symptoms is still a matter of debate.This study shows an approach for measuring retrospective adherence based on a mobile app. This represent a novel approach also for analyzing medication taking behavior in a real-world setting. This article is protected by copyright. All rights reserved.

Journal article

Farne H, Groves H, Gill S, stokes I, Mccolloch S, karoly E, Trujillo-Torralbo M, Johnston S, Mallia P, Tregoning Jet al., 2018, Comparative metabolomic sampling of upper and lower airways by four different methods to identify biochemicals that may support bacterial growth, Frontiers in Cellular and Infection Microbiology, Vol: 8, ISSN: 2235-2988

Bacteria need nutrients from the host environment to survive, yet we know little about which biochemicals are present in the airways (the metabolome), which of these biochemicals are essential for bacterial growth and how they change with airway disease. The aims of this pilot study were to develop and compare methodologies for sampling the upper and lower airway metabolomes and to identify biochemicals present in the airways that could potentially support bacterial growth. Eight healthy human volunteers were sampled by four methods: two standard approaches - nasal lavage and induced sputum, and two using a novel platform, synthetic adsorptive matrix (SAM) strips—nasosorption and bronchosorption. Collected samples were analyzed by Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy (UPLC-MS/MS). Five hundred and eighty-one biochemicals were recovered from the airways belonging to a range of metabolomic super-pathways. We observed significant differences between the sampling approaches. Significantly more biochemicals were recovered when SAM strips were used, compared to standard sampling techniques. A range of biochemicals that could support bacterial growth were detected in the different samples. This work demonstrates for the first time that SAM strips are a highly effective method for sampling the airway metabolome. This work will assist further studies to understand how changes in the airway metabolome affect bacterial infection in patients with underlying airway disease.

Journal article

Finney LJ, Belchamber KBR, Fenwick PS, Kemp SV, Edwards MR, Mallia P, Donaldson G, Johnston SL, Donnelly LE, Wedzicha JAet al., 2018, Human Rhinovirus Impairs the Innate Immune Response to Bacteria in Alveolar Macrophages in COPD, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X

Rationale Human rhinovirus (HRV) is a common cause of COPD exacerbations. Secondary bacterial infection is associated with more severe symptoms and delayed recovery. Alveolar macrophages clear bacteria from the lung and maintain lung homeostasis through cytokine secretion. These processes are defective in COPD. The effect of HRV on macrophage function is unknown. Objectives To investigate the effect of HRV on phagocytosis and cytokine response to bacteria by alveolar macrophages and monocyte derived macrophages (MDM) in COPD and healthy controls. Methods Alveolar macrophages were obtained by bronchoscopy and MDM by adherence. Macrophages were exposed to HRV 16 (multiplicity of infection 5), polyI:C 30μg/ml, interferon (IFN)-β 10μg/ml, IFN-γ 10μg/ml or medium control for 24 hours. Phagocytosis of fluorescently-labelled Haemophilus influenzae or Streptococcus pneumoniae was assessed by fluorimetry. CXCL8, TNF and IL-10 release was measured by ELISA. Main Results HRV significantly impaired phagocytosis of H. influenzae by 23% in MDM (n=37) and 18% in alveolar macrophages (n=20) in COPD. HRV also significantly reduced phagocytosis of S. pneumoniae by 33% in COPD MDM. There was no effect in healthy controls. Phagocytosis of H. influenzae was impaired by polyI:C but not IFN-β or IFN-γ. HRV significantly reduced cytokine responses to H. influenzae. The IL-10 response to H. influenzae was significantly impaired by polyI:C, IFN-β and IFN-γ. Conclusions HRV impairs phagocytosis of bacteria in COPD which may lead to an outgrowth of bacteria. HRV also impairs cytokine responses to bacteria via the TLR3/IFN pathway which may prevent resolution of inflammation leading to prolonged exacerbations in COPD.

Journal article

Finney LJ, Belchamber KBR, Kemp SV, Fenwick P, Mallia P, Donaldson G, Johnston SL, Donnelly L, Wedzicha JAet al., 2018, HUMAN RHINOVIRUS IMPAIRS THE INNATE IMMUNE RESPONSE TO BACTERIA IN MACROPHAGES IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A9-A9, ISSN: 0040-6376

Conference paper

Jolliffe DA, Greiller CL, Mein CA, Hoti M, Bakhsoliani E, Telcian AG, Simpson A, Barnes NC, Curtin JA, Custovic A, Johnston SL, Griffiths CJ, Walton RT, Martineau ARet al., 2018, Vitamin D receptor genotype influences risk of upper respiratory infection, British Journal of Nutrition, Vol: 120, Pages: 891-900, ISSN: 1475-2662

SNP in the vitamin D receptor (VDR) gene is associated with risk of lower respiratory infections. The influence of genetic variation in the vitamin D pathway resulting in susceptibility to upper respiratory infections (URI) has not been investigated. We evaluated the influence of thirty-three SNP in eleven vitamin D pathway genes (DBP, DHCR7, RXRA, CYP2R1, CYP27B1, CYP24A1, CYP3A4, CYP27A1, LRP2, CUBN and VDR) resulting in URI risk in 725 adults in London, UK, using an additive model with adjustment for potential confounders and correction for multiple comparisons. Significant associations in this cohort were investigated in a validation cohort of 737 children in Manchester, UK. In all, three SNP in VDR (rs4334089, rs11568820 and rs7970314) and one SNP in CYP3A4 (rs2740574) were associated with risk of URI in the discovery cohort after adjusting for potential confounders and correcting for multiple comparisons (adjusted incidence rate ratio per additional minor allele ≥1·15, P for trend ≤0·030). This association was replicated for rs4334089 in the validation cohort (P for trend=0·048) but not for rs11568820, rs7970314 or rs2740574. Carriage of the minor allele of the rs4334089 SNP in VDR was associated with increased susceptibility to URI in children and adult cohorts in the United Kingdom.

Journal article

Bousquet J, Arnavielhe S, Bedbrook A, Bewick M, Laune D, Mathieu-Dupas E, Murray R, Onorato GL, Pepin JL, Picard R, Portejoie F, Costa E, Fonseca J, Lourenco O, Morais-Almeida M, Todo-Bom A, Cruz AA, da Silva J, Serpa FS, Illario M, Menditto E, Cecchi L, Monti R, Napoli L, Ventura MT, De Feo G, Larenas-Linnemann D, Fuentes Perez M, Huerta Villabolos YR, Rivero-Yeverino D, Rodriguez-Zagal E, Amat F, Annesi-Maesano I, Bosse I, Demoly P, Devillier P, Fontaine JF, Just J, Kuna TP, Samolinski B, Valiulis A, Emuzyte R, Kvedariene V, Ryan D, Sheikh A, Schmidt-Grendelmeier P, Klimek L, Pfaar O, Bergmann KC, Mosges R, Zuberbier T, Roller-Wirnsberger RE, Tomazic P, Fokkens WJ, Chavannes NH, Reitsma S, Anto JM, Cardona V, Dedeu T, Mullol J, Haahtela T, Salimaki J, Toppila-Salmi S, Valovirta E, Gemicioglu B, Yorgancioglu A, Papadopoulos N, Prokopakis EP, Bosnic-Anticevich S, O'Hehir R, Ivancevich JC, Neffen H, Zernotti E, Kull I, Melen E, Wickman M, Bachert C, Hellings P, Palkonen S, Bindslev-Jensen C, Eller E, Waserman S, Sova M, De Vries G, van Eerd M, Agache I, Casale T, Dykewickz M, Naclerio RN, Okamoto Y, Wallace DVet al., 2018, MASK 2017: ARIA digitally-enabled, integrated, person-centred care for rhinitis and asthma multimorbidity using real-world-evidence, Clinical and Translational Allergy, Vol: 8, ISSN: 2045-7022

mHealth, such as apps running on consumer smart devices is becoming increasingly popular and has the potential to profoundly affect healthcare and health outcomes. However, it may be disruptive and results achieved are not always reaching the goals. Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline using the best evidence-based approach to care pathways suited to real-life using mobile technology in allergic rhinitis (AR) and asthma multimorbidity. Patients largely use over-the-counter medications dispensed in pharmacies. Shared decision making centered around the patient and based on self-management should be the norm. Mobile Airways Sentinel networK (MASK), the Phase 3 ARIA initiative, is based on the freely available MASK app (the Allergy Diary, Android and iOS platforms). MASK is available in 16 languages and deployed in 23 countries. The present paper provides an overview of the methods used in MASK and the key results obtained to date. These include a novel phenotypic characterization of the patients, confirmation of the impact of allergic rhinitis on work productivity and treatment patterns in real life. Most patients appear to self-medicate, are often non-adherent and do not follow guidelines. Moreover, the Allergy Diary is able to distinguish between AR medications. The potential usefulness of MASK will be further explored by POLLAR (Impact of Air Pollution on Asthma and Rhinitis), a new Horizon 2020 project using the Allergy Diary.

Journal article

Tang HHF, Teo SM, Belgrave DCM, Evans MD, Jackson DJ, Brozynska M, Kusel MMH, Johnston SL, Gern JE, Lemanske RF, Simpson A, Custovic A, Sly PD, Holt PG, Holt KE, Inouye Met al., 2018, Trajectories of childhood immune development and respiratory health relevant to asthma and allergy, eLife, Vol: 7, ISSN: 2050-084X

Events in early life contribute to subsequent risk of asthma; however, the causes andtrajectories of childhood wheeze are heterogeneous and do not always result in asthma. Similarly,not all atopic individuals develop wheeze, and vice versa. The reasons for these differences areunclear. Using unsupervised model-based cluster analysis, we identified latent clusters within aprospective birth cohort with deep immunological and respiratory phenotyping. We characterisedeach cluster in terms of immunological profile and disease risk, and replicated our results inexternal cohorts from the UK and USA. We discovered three distinct trajectories, one of which is ahigh-risk ‘atopic’ cluster with increased propensity for allergic diseases throughout childhood.Atopy contributes varyingly to later wheeze depending on cluster membership. Our findingsdemonstrate the utility of unsupervised analysis in elucidating heterogeneity in asthmapathogenesis and provide a foundation for improving management and prevention of childhoodasthma.

Journal article

Makris S, Johnston S, 2018, Recent advances in understanding rhinovirus immunity, F1000Research, Vol: 7, ISSN: 2046-1402

Rhinoviruses are the most common cause of upper respiratory tract infections. However, they can induce exacerbations of chronic obstructive pulmonary disease and asthma, bronchiolitis in infants, and significant lower respiratory tract infections in children, the immunosuppressed, and the elderly. The large number of rhinovirus strains (currently about 160) and their antigenic diversity are significant obstacles in vaccine development. The phenotype of immune responses induced during rhinovirus infection can affect disease severity. Recognition of rhinovirus and a balance of innate responses are important factors in rhinovirus-induced morbidity. Immune responses to rhinovirus infections in healthy individuals are typically of the T helper type 1 (Th1) phenotype. However, rhinovirus-driven asthma exacerbations are additionally characterised by an amplified Th2 immune response and airway neutrophilia. This commentary focuses on recent advances in understanding immunity toward rhinovirus infection and how innate and adaptive immune responses drive rhinovirus-induced asthma exacerbations.

Journal article

Teo SM, Tang HHF, Mok D, Judd LM, Watts SC, Pham K, Holt BJ, Kusel M, Serralha M, Troy N, Bochkov YA, Grindle K, Lemanske RF, Johnston SL, Gern JE, Sly PD, Holt PG, Holt KE, Inouye Met al., 2018, Airway microbiota dynamics uncover a critical window for interplay of pathogenic bacteria and allergy in childhood respiratory disease, Cell Host and Microbe, Vol: 24, Pages: 341-352.e5, ISSN: 1931-3128

Repeated cycles of infection-associated lower airway inflammation drive the pathogenesis of persistent wheezing disease in children. In this study, the occurrence of acute respiratory tract illnesses (ARIs) and the nasopharyngeal microbiome (NPM) were characterized in 244 infants through their first five years of life. Through this analysis, we demonstrate that >80% of infectious events involve viral pathogens, but are accompanied by a shift in the NPM toward dominance by a small range of pathogenic bacterial genera. Unexpectedly, this change frequently precedes the detection of viral pathogens and acute symptoms. Colonization of illness-associated bacteria coupled with early allergic sensitization is associated with persistent wheeze in school-aged children, which is the hallmark of the asthma phenotype. In contrast, these bacterial genera are associated with "transient wheeze" that resolves after age 3 years in non-sensitized children. Thus, to complement early allergic sensitization, monitoring NPM composition may enable early detection and intervention in high-risk children.

Journal article

Tregoning JS, Mallia P, Webber J, Gill SK, Trujillo-Torralbo, Calderazzo MA, Finney L, Bakhsoliani E, Farne H, Singanayagam A, Footitt J, Hewitt R, Kebadze, Aniscenko J, Padmanaban V, Molyneaux PL, Adcock, Barnes PJ, Ito K, Elkin SL, Kon OM, Cookson WO, MOffatt MF, Johnston SLet al., 2018, Role of airway glucose in bacterial infections in chronic obstructive pulmonary disease, Journal of Allergy and Clinical Immunology, Vol: 142, Pages: 815-823.e6, ISSN: 0091-6749

BackgroundPatients with chronic obstructive pulmonary disease (COPD) have increased susceptibility to respiratory tract infection, which contributes to disease progression and mortality, but mechanisms of increased susceptibility to infection remain unclear.ObjectivesThe aim of this study was to determine whether glucose concentrations were increased in airway samples (nasal lavage fluid, sputum, and bronchoalveolar lavage fluid) from patients with stable COPD and to determine the effects of viral infection on sputum glucose concentrations and how airway glucose concentrations relate to bacterial infection.MethodsWe measured glucose concentrations in airway samples collected from patients with stable COPD and smokers and nonsmokers with normal lung function. Glucose concentrations were measured in patients with experimentally induced COPD exacerbations, and these results were validated in patients with naturally acquired COPD exacerbations. Relationships between sputum glucose concentrations, inflammatory markers, and bacterial load were examined.ResultsSputum glucose concentrations were significantly higher in patients with stable COPD compared with those in control subjects without COPD. In both experimental virus-induced and naturally acquired COPD exacerbations, sputum and nasal lavage fluid glucose concentrations were increased over baseline values. There were significant correlations between sputum glucose concentrations and sputum inflammatory markers, viral load, and bacterial load. Airway samples with higher glucose concentrations supported more Pseudomonas aeruginosa growth in vitro.ConclusionsAirway glucose concentrations are increased in patients with stable COPD and further increased during COPD exacerbations. Increased airway glucose concentrations might contribute to bacterial infections in both patients with stable and those with exacerbated COPD. This has important implications for the development of nonantibiotic therapeutic strategies for the prev

Journal article

Lan F, Zhang N, Holtappels G, De Ruyck N, Krysko O, Van Crombruggen K, Braun H, Johnston SL, Papadopoulos NG, Zhang L, Bachert Cet al., 2018, Staphylococcus aureus Induces a Mucosal Type 2 Immune Response via Epithelial Cell-derived Cytokines, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 198, Pages: 452-463, ISSN: 1073-449X

Journal article

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