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
to

526 results found

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

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

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 HT, Gill SK, Stokes I, McCulloch S, Karoly E, Trujillo-Torralbo M-B, Johnston SL, Mallia P, Tregoning JSet 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

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., Am J Respir Crit Care Med

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

Lan F, Zhong H, Zhang N, Johnston SL, Wen W, Papadopoulos N, Zhang L, Bachert Cet al., 2018, IFN-λ1 enhances Staphylococcus aureus clearance in healthy nasal mucosa but not in nasal polyps., J Allergy Clin Immunol

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by TH2-skewed inflammation and increased colonization by Staphylococcus aureus. IFN-λ1 is known for its antiviral activity, but there is little information on its antibacterial role. OBJECTIVE: We sought to determine the expression and release of IFN-λ1 from nasal mucosal tissue of healthy subjects and patients with CRSwNP on exposure to S aureus and assess its potential role in antibacterial defense mechanisms. METHODS: Nasal tissue from healthy subjects and patients with CRSwNP was exposed to S aureus, and we assessed expression of IFN-λ1, MUC5AC, and MUC5B. THP1-derived macrophages incubated with or without IFN-λ1 were assessed for uptake and killing of S aureus and expression of lysosomal-associated membrane protein 1 and intracellular reactive oxidase substrate (ROS), the IFN-λ1 receptor IL-28 receptor (IL-28R), and the Janus kinase/signal transducer and activator of transcription (STAT) 1 pathway by means of immunofluorescence staining. RESULTS: S aureus infection increased IFN-λ1 expression in tissue from patients with CRSwNP. IFN-λ1 (10 ng/mL) significantly decreased the number of S aureus colony-forming units in healthy control tissue but not in tissue from patients with CRSwNP and upregulated MUC5AC and MUC5B expression in control tissue on S aureus infection. IFN-λ1 stimulation increased intracellular killing of S aureus in THP1-derived macrophages and substantially increased lysosomal-associated membrane protein 1, IL-28R, ROS, and STAT signaling in macrophages incubated with S aureus. All of these effects were attenuated by blocking IL-28R and ROS activities. CONCLUSIONS: IFN-λ1 favors clearance of S aureus in healthy nasal mucosa and enhances antibacterial function of macrophages through IFN-λ1-IL-28R-ROS-Janus kinase-STAT signaling pathways.

JOURNAL ARTICLE

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: 0007-1145

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

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

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, Cepeda Sarabia AM, Chavannes NH, Cecchi L, Correia de Sousa J, 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, Guzmán 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, Lourenço O, Mahboub B, Mair A, Menditto E, Milenkovic B, Morais-Almeida M, Mösges 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, Salimäki J, Samolinski B, Sanchez-Borges M, Schunemann HJ, Sheikh A, Sisul J-C, Rajabian-Söderlund 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, Mobile Airways Sentinel Network MASK Study Groupet al., 2018, Allergic Rhinitis and its Impact on Asthma (ARIA) Phase 4 (2018): Change management in allergic rhinitis and asthma multimorbidity using mobile technology., J Allergy Clin Immunol

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

Makris S, Johnston S, 2018, Recent advances in understanding rhinovirus immunity, F1000Research, 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 & MICROBE, Vol: 24, Pages: 341-+, ISSN: 1931-3128

JOURNAL ARTICLE

Mallia P, Webber J, Gill SK, Trujillo-Torralbo M-B, Calderazzo MA, Finney L, Bakhsoliani E, Fame H, Singanayagam A, Footitt J, Hewitt R, Kebadze T, Aniscenko J, Padmanaban V, Molyneaux PL, Adcock IM, Barnes PJ, Ito K, Elkin SL, Kon OM, Cookson WO, Moffat MF, Johnston SL, Tregoning JSet al., 2018, Role of airway glucose in bacterial infections in patients with chronic obstructive pulmonary disease, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 142, Pages: 815-+, ISSN: 0091-6749

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

Potaczek DP, Unger SD, Zhang N, Taka S, Michel S, Akdağ N, Lan F, Helfer M, Hudemann C, Eickmann M, Skevaki C, Megremis S, Sadewasser A, Alashkar Alhamwe B, Alhamdan F, Akdis M, Edwards MR, Johnston SL, Akdis CA, Becker S, Bachert C, Papadopoulos NG, Garn H, Renz Het al., 2018, Development and characterization of DNAzyme candidates demonstrating significant efficiency against human rhinoviruses., J Allergy Clin Immunol

BACKGROUND: Infections with human rhinoviruses (RVs) are responsible for millions of common cold episodes and the majority of asthma exacerbations, especially in childhood. No drugs specifically targeting RVs are available. OBJECTIVE: We sought to identify specific anti-RV molecules based on DNAzyme technology as candidates to a clinical study. METHODS: A total of 226 candidate DNAzymes were designed against 2 regions of RV RNA genome identified to be sufficiently highly conserved between virus strains (ie, the 5'-untranslated region and cis-acting replication element) by using 3 test strains: RVA1, RVA16, and RVA29. All DNAzymes were screened for their cleavage efficiency against in vitro-expressed viral RNA. Those showing any catalytic activity were subjected to bioinformatic analysis of their reverse complementarity to 322 published RV genomic sequences. Further molecular optimization was conducted for the most promising candidates. Cytotoxic and off-target effects were excluded in HEK293 cell-based systems. Antiviral efficiency was analyzed in infected human bronchial BEAS-2B cells and ex vivo-cultured human sinonasal tissue. RESULTS: Screening phase-generated DNAzymes characterized by either good catalytic activity or by high RV strain coverage but no single molecule represented a satisfactory combination of those 2 features. Modifications in length of the binding domains of 2 lead candidates, Dua-01(-L12R9) and Dua-02(-L10R11), improved their cleavage efficiency to an excellent level, with no loss in eminent strain coverage (about 98%). Both DNAzymes showed highly favorable cytotoxic/off-target profiles. Subsequent testing of Dua-01-L12R9 in BEAS-2B cells and sinonasal tissue demonstrated its significant antiviral efficiency. CONCLUSIONS: Effective and specific management of RV infections with Dua-01-L12R9 might be useful in preventing asthma exacerbations, which should be verified by clinical trials.

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 AB, Alhamdan F, Akdis M, Edwards MR, Johnston SL, Akdis CA, Becker S, Bachert C, Papadopoulos NG, Garn H, Renz Het al., 2018, Development and characterization of effective DNAzymes against human rhinoviruses, Congress of the European-Academy-of-Allergy-and-Clinical-Immunology (EAACI), Publisher: WILEY, Pages: 370-370, ISSN: 0105-4538

CONFERENCE PAPER

Chairakaki A-D, Saridaki M-I, Pyrillou K, Mouratis M-A, Koltsida O, Walton RP, Bartlett NW, Stavropoulos A, Boon L, Rovina N, Papadopoulos NG, Johnston SL, Andreakos Eet al., 2018, Plasmacytoid dendritic cells drive acute asthma exacerbations, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 142, Pages: 542-+, ISSN: 0091-6749

JOURNAL ARTICLE

Singanayagam A, Glanville N, Girkin JL, Ching YM, Marcellini A, Porter JD, Toussaint M, Walton RP, Finney LJ, Aniscenko J, Zhu J, Trujillo-Torralbo M-B, Calderazzo MA, Grainge C, Loo S-L, Veerati PC, Pathinayake PS, Nichol KS, Reid AT, James PL, Solari R, Wark PAB, Knight DA, Moffatt MF, Cookson WO, Edwards MR, Mallia P, Bartlett NW, Johnston SLet al., 2018, Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations, NATURE COMMUNICATIONS, Vol: 9, ISSN: 2041-1723

JOURNAL ARTICLE

Mousnier A, Bell AS, Swieboda DP, Morales-Sanfrutos J, Perez-Dorado I, Brannigan JA, Newman J, Ritzefeld M, Hutton JA, Guedan A, Asfor AS, Robinson SW, Hopkins-Navratilova I, Wilkinson AJ, Johnston SL, Leatherbarrow RJ, Tuthill TJ, Solari R, Tate EWet al., 2018, Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus, NATURE CHEMISTRY, Vol: 10, Pages: 599-606, ISSN: 1755-4330

JOURNAL ARTICLE

Dunning J, Blankley S, Hoang LT, Cox M, Graham CM, James PL, Bloom CI, Chaussabel D, Banchereau J, Brett SJ, Moffatt MF, O'Garra A, Openshaw PJMet al., 2018, Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza, NATURE IMMUNOLOGY, Vol: 19, Pages: 625-+, ISSN: 1529-2908

JOURNAL ARTICLE

Custovic A, Belgrave D, Lin L, Bakhsoliani E, Telcian AG, Solari R, Murray CS, Walton RP, Curtin J, Edwards MR, Simpson A, Rattray M, Johnston SLet al., 2018, Cytokine Responses to Rhinovirus and Development of Asthma, Allergic Sensitization, and Respiratory Infections during Childhood, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 197, Pages: 1265-1274, ISSN: 1073-449X

JOURNAL ARTICLE

Ghebre MA, Pang PH, Diver S, Desai D, Bafadhel M, Haldar K, Kebadze T, Cohen S, Newbold P, Rapley L, Woods J, Rugman P, Pavord ID, Johnston SL, Barer M, May RD, Brightling CEet al., 2018, Biological exacerbation clusters demonstrate asthma and COPD overlap with distinct mediator and microbiome profiles., Journal of Allergy and Clinical Immunology, ISSN: 0091-6749

BACKGROUND: Exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous. OBJECTIVE: We sought to investigate the sputum cellular, mediator, and microbiome profiles of both asthma and COPD exacerbations. METHODS: Patients with severe asthma or moderate-to-severe COPD were prospectively recruited to a single centre. Sputum mediators were available in 32 asthma and 73 COPD patients assessed at exacerbation. Biologic clusters were determined using factor and cluster analyses on a panel of sputum mediators. Patterns of clinical parameters, sputum mediators, and microbiome communities were assessed across the identified clusters. RESULTS: The asthma and COPD patients had different clinical characteristics and inflammatory profiles, but similar microbial ecology. Three exacerbation biologic clusters were identified. Cluster 1 was COPD predominant, with 27 COPD and 7 asthma patients exhibiting elevated blood and sputum neutrophil counts, proinflammatory mediators (IL-1β, IL-6, IL-6R, TNFα, TNF-R1, TNF-R2, and VEGF), and proportion of the bacterial phylum Proteobacteria. Cluster 2 had 10 asthma and 17 COPD patients with elevated blood and sputum eosinophil counts, Type 2 (T2) mediators (IL-5, IL-13, CCL13, CCL17, and CCL26), and proportion of the bacterial phylum Bacteroidetes. Cluster 3 had 15 asthma and 29 COPD subjects with elevated Type 1 (T1) mediators (CXCL10, CXCL11, and IFN-ϒ) and proportions of phyla Actinobacteria and Firmicutes. CONCLUSIONS: A biologic clustering approach revealed three subgroups of asthma and COPD exacerbations each with different percentages of overlapping asthma and COPD patients. The sputum mediator and microbiome profiles were distinct between clusters. CLINICAL IMPLICATIONS: Sputum mediator and microbiome profiling can determine the distinct and overlapping asthma and COPD biologic exacerbation clusters, highlighting the heterogeneity of these exacerbations.

JOURNAL ARTICLE

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., Bronchial mucosal Interferon-α/β and pattern recognition receptor expression in experimental rhinovirus-induced asthma exacerbations, Journal of Allergy and Clinical Immunology, 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

Silkoff PE, Flavin S, Gordon R, Loza MJ, Sterk PJ, Lutter R, Diamant Z, Turner RB, Lipworth BJ, Proud D, Singh D, Eich A, Backer V, Gern JE, Herzmann C, Halperin SA, Mensinga TT, Del Vecchio AM, Branigan P, San Mateo L, Baribaud F, Barnathan ES, Johnston SLet al., 2018, Toll-like receptor 3 blockade in rhinovirus-induced experimental asthma exacerbations: A randomized controlled study, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 141, Pages: 1220-1230, ISSN: 0091-6749

JOURNAL ARTICLE

McErlean P, Kelly A, Dhariwal J, Kirtland M, Watson J, Ranz Jimenez I, Saxena A, Cousins D, Solari R, Edwards M, Johnston S, Lavender Pet al., 2018, Genome-wide profiling of an enhancer-associated histone modification reveals the influence of asthma on the epigenome of the airway epithelium., Biorxiv

Asthma is a chronic airway disease driven by complex genetic-environmental interactions. The role of epigenetic modifications in bronchial epithelial cells (BECs) in asthma is poorly understood. We undertook genome-wide profiling of the enhancer-associated histone modification H3K27ac in BECs from people with asthma and healthy controls. We identified 49,903 regions exhibiting differential H3K27ac enrichment in asthma, clustered at genes associated with type-2-high asthma (CLCA1) and epithelial processes (EMT). Asthma dramatically influenced the BEC enhancer landscape and we identified asthma-associated Super-Enhancers encompassing genes encoding transcription factors (TP63) and enzymes regulating lipid metabolism (NOX4). We integrated published protein, epigenomic and transcriptomic datasets and identified epithelium-specific transcription factors associated with H3K27ac in asthma (TP73) and dynamic relationships between asthma-associated changes in H3K27ac, DNA methylation, genetic susceptibility and transcriptional profiles. Finally, we used a CRISPR-based approach to recapitulate the H3K27ac-asthma landscape in vitro and provide proof of principal that asthma-associated gene expression (SERPINB2) is driven in part by aberrant histone acetylation, validating the combination of genome-wide and epigenome-editing approaches in deciphering the molecular mechanisms underlying asthma pathogenesis.

JOURNAL ARTICLE

Moskwa S, Piotrowski W, Marczak J, Pawelczyk M, Lewandowska-Polak A, Jarzebska M, Brauncajs M, Globinska A, Gorski P, Papadopoulos NG, Edwards MR, Johnston SL, Kowalski MLet al., 2018, Innate Immune Response to Viral Infections in Primary Bronchial Epithelial Cells is Modified by the Atopic Status of Asthmatic Patients, ALLERGY ASTHMA & IMMUNOLOGY RESEARCH, Vol: 10, Pages: 144-154, ISSN: 2092-7355

JOURNAL ARTICLE

Delgado-Eckert E, Fuchs O, Kumar N, Pekkanen J, Dalphin J-C, Riedler J, Lauener R, Kabesch M, Kupczyk M, Dahlen S-E, von Mutius E, Frey Uet al., 2018, Functional phenotypes determined by fluctuation-based clustering of lung function measurements in healthy and asthmatic cohort participants, THORAX, Vol: 73, Pages: 107-115, ISSN: 0040-6376

JOURNAL ARTICLE

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