Imperial College London

Professor William Cookson

Faculty of MedicineNational Heart & Lung Institute

Professor of Genomic Medicine
 
 
 
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Contact

 

+44 (0)20 7594 2943w.cookson

 
 
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Location

 

400Guy Scadding BuildingRoyal Brompton Campus

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Summary

 

Publications

Publication Type
Year
to

352 results found

Cookson W, Nastase A, Mandal A, Lu SK, Abunathan H, Morris-Rosendahl D, Zhand YZ, Sun X-M, Gennatas S, Rintoul R, Edwards M, Bowman A, Chernova T, Benepal T, Lim E, Newman Taylor A, Nicholson A, Popat S, Willis A, MacFarlane M, Lathrop M, Bowcock A, Moffatt Met al., 2021, Integrated genomics point to immune vulnerabilities in pleural mesothelioma, Scientific Reports, ISSN: 2045-2322

Journal article

Cookson W, Turek E, Moffatt M, Cox M, Hunter M, Hui J, James P, Willis-Owen S, Cuthbertson L, James A, Musk Aet al., 2021, Airway microbial communities, smoking and asthma in a general population sample, EBioMedicine, Vol: 71, Pages: 1-9, ISSN: 2352-3964

BackgroundNormal airway microbial communities play a central role in respiratory health but arepoorly characterized. Cigarette smoking is the dominant global environmental influenceon lung function, and asthma has become the most prevalent chronic respiratorydisease worldwide. Both conditions have major microbial components that areincompletely defined.MethodsWe investigated airway bacterial communities in a general population sample of 529Australian adults. Posterior oropharyngeal swabs were analyzed by sequencing of the16S rRNA gene. The microbiota were characterized according to their prevalence,abundance and network memberships.FindingsThe microbiota were similar across the general population, and were stronglyorganized into co-abundance networks. Smoking associated with diversity loss,negative effects on abundant taxa, profound alterations to network structure andexpansion of Streptococcus spp. By contrast, the asthmatic microbiota wereselectively affected by an increase in Neisseria spp. and by reduced numbers of lowabundance but prevalent organisms.InterpretationOur study shows that the healthy airway microbiota in this population were containedwithin a highly structured ecosystem, suggesting balanced relationships between themicrobiome and human host factors. The marked abnormalities in smokers maycontribute to chronic obstructive pulmonary disease (COPD) and lung cancer. Thenarrow spectrum of abnormalities in asthmatics encourages investigation of damagingand protective effects of specific bacteria.

Journal article

Domingo-Sabugo C, Willis-Owen SAG, Mandal A, Nastase A, Dwyer S, Brambilla C, Gálvez JH, Zhuang Q, Popat S, Eveleigh R, Munter M, Lim E, Nicholson AG, Lathrop M, Cookson WOC, Moffatt MFet al., 2021, Distinct pancreatic and neuronal Lung Carcinoid molecular subtypes revealed by integrative omic analysis

<jats:title>Summary</jats:title><jats:p>Lung Carcinoids (L-CDs) are uncommon low-grade neuroendocrine tumours that are only recently becoming characterised at the molecular level. Notably data on the molecular events that precipitate altered gene expression programmes are very limited. Here we have identified two discrete L-CD subtypes from transcriptomic and whole-genome DNA methylation data, and comprehensively defined their molecular profiles using Whole-Exome Sequencing (WES) and Single Nucleotide Polymorphism (SNP) genotyping. Subtype (Group) 1 features upregulation of neuronal markers (L-CD-NeU) and is characterised by focal spindle cell morphology, peripheral location (71%), high mutational load (<jats:italic>P</jats:italic>=3.4×10<jats:sup>−4</jats:sup>), recurrent copy number alterations and is enriched for Atypical Lung Carcinoids. Group 2 (L-CD-PanC) are centrally located and feature upregulation of pancreatic and metabolic pathway genes concordant with promoter hypomethylation of beta cell and genes related to insulin secretion (<jats:italic>P</jats:italic>&lt;1×10<jats:sup>−6</jats:sup>). L-CD-NeU tumours harbour mutations in chromatin remodelling and in SWI/SNF complex members, while L-CD-PanC tumours show aflatoxin mutational signatures and significant DNA methylation loss genome-wide, particularly enriched in repetitive elements (<jats:italic>P</jats:italic>&lt;2.2 × 10<jats:sup>−16</jats:sup>). Our findings provide novel insights into the distinct mechanisms of epigenetic dysregulation in these lung malignancies, potentially opening new avenues for biomarker selection and treatment in L-CD patients.</jats:p>

Journal article

Willis-Owen S, Domingo Sabugo C, Starren E, Liang L, Freidin M, Arseneault M, Zhang Y, Kiong Lu S, Popat S, Lim E, Nicholson A, Riazalhosseini Y, Lathrop M, Cookson W, Moffatt Met al., 2021, Y disruption, autosomal hypomethylation and poor male lung cancer survival, Scientific Reports, Vol: 11, ISSN: 2045-2322

Lung cancer is the most frequent cause of cancer death worldwide. It affects more men than women, and men generally have worse survival outcomes. We compared gene co-expression networks in affected and unaffected lung tissue from 126 consecutive patients with Stage IA–IV lung cancer undergoing surgery with curative intent. We observed marked degradation of a sex-associated transcription network in tumour tissue. This disturbance, detected in 27.7% of male tumours in the discovery dataset and 27.3% of male tumours in a further 123-sample replication dataset, was coincident with partial losses of the Y chromosome and extensive autosomal DNA hypomethylation. Central to this network was the epigenetic modifier and regulator of sexually dimorphic gene expression, KDM5D. After accounting for prognostic and epidemiological covariates including stage and histology, male patients with tumour KDM5D deficiency showed a significantly increased risk of death (Hazard Ratio [HR] 3.80, 95% CI 1.40–10.3, P = 0.009). KDM5D deficiency was confirmed as a negative prognostic indicator in a further 1100 male lung tumours (HR 1.67, 95% CI 1.4–2.0, P = 1.2 × 10–10). Our findings identify tumour deficiency of KDM5D as a prognostic marker and credible mechanism underlying sex disparity in lung cancer.

Journal article

Laura G, Liu Y, Fernandes K, Willis-Owen SAG, Ito K, Cookson WO, Moffatt MF, Zhang Yet al., 2021, ORMDL3 regulates poly I:C induced inflammatory responses in airway epithelial cells, BMC Pulmonary Medicine, Vol: 21, ISSN: 1471-2466

Background:Oroscomucoid 3 (ORMDL3) has been linked to susceptibility of childhood asthma and respiratory viral infection. Polyinosinic-polycytidylic acid (poly I:C) is a synthetic analog of viral double-stranded RNA, a toll-like receptor 3 (TLR3) ligand and mimic of viral infection.Methods:To investigate the functional role of ORMDL3 in the poly I:C-induced inflammatory response in airway epithelial cells, ORMDL3 knockdown and over-expression models were established in human A549 epithelial cells and primary normal human bronchial epithelial (NHBE) cells. The cells were stimulated with poly I:C or the Th17 cytokine IL-17A. IL-6 and IL-8 levels in supernatants, mRNA levels of genes in the TLR3 pathway and inflammatory response from cell pellets were measured. ORMDL3 knockdown models in A549 and BEAS-2B epithelial cells were then infected with live human rhinovirus (HRV16) followed by IL-6 and IL-8 measurement.Results:ORMDL3 knockdown and over-expression had little influence on the transcript levels of TLR3 in airway epithelial cells. Time course studies showed that ORMDL3-deficient A549 and NHBE cells had an attenuated IL-6 and IL-8 response to poly I:C stimulation. A549 and NHBE cells over-expressing ORMDL3 released relatively more IL-6 and IL-8 following poly I:C stimulation. IL-17A exhibited a similar inflammatory response in ORMDL3 knockdown and over-expressing cells, but co-stimulation of poly I:C and IL-17A did not significantly enhance the IL-6 and IL-8 response. Transcript abundance of IFNB following poly I:C stimulation was not significantly altered by ORMDL3 knockdown or over-expression. Dampening of the IL-6 response by ORMDL3 knockdown was confirmed in HRV16 infected BEAS-2B and A549 cells.Conclusions:ORMDL3 regulates the viral inflammatory response in airway epithelial cells via mechanisms independent of the TLR3 pathway.

Journal article

Cuthbertson L, Felton I, James P, Cox MJ, Bilton D, Schelenz S, Loebinger MR, Cookson WOC, Simmonds NJ, Moffatt MFet al., 2021, The fungal airway microbiome in cystic fibrosis and non-cystic fibrosis bronchiectasis, Journal of Cystic Fibrosis, Vol: 20, Pages: 295-302, ISSN: 1569-1993

BackgroundThe prevalence of fungal disease in cystic fibrosis (CF) and non-CF bronchiectasis is increasing and the clinical spectrum is widening. Poor sensitivity and a lack of standard diagnostic criteria renders interpretation of culture results challenging. In order to develop effective management strategies, a more accurate and comprehensive understanding of the airways fungal microbiome is required. The study aimed to use DNA sequences from sputum to assess the load and diversity of fungi in adults with CF and non-CF bronchiectasis.MethodsNext generation sequencing of the ITS2 region was used to examine fungal community composition (n = 176) by disease and underlying clinical subgroups including allergic bronchopulmonary aspergillosis, chronic necrotizing pulmonary aspergillosis, non-tuberculous mycobacteria, and fungal bronchitis. Patients with no known active fungal disease were included as disease controls.ResultsITS2 sequencing greatly increased the detection of fungi from sputum. In patients with CF fungal diversity was lower, while burden was higher than those with non-CF bronchiectasis. The most common operational taxonomic unit (OTU) in patients with CF was Candida parapsilosis (20.4%), whereas in non-CF bronchiectasis sputum Candida albicans (21.8%) was most common. CF patients with overt fungal bronchitis were dominated by Aspergillus spp., Exophiala spp., Candida parapsilosis or Scedosporium spp.ConclusionThis study provides a framework to more accurately characterize the extended spectrum of fungal airways diseases in adult suppurative lung diseases.

Journal article

Feng Y-CA, Guo Y, Pain L, Lathrop GM, Laprise C, Moffatt MF, Cookson WOCM, Liang Let al., 2020, Estimating cell-type-specific DNA methylation effects in heterogeneous cellular populations, EPIGENOMICS, Vol: 13, Pages: 87-97, ISSN: 1750-1911

Journal article

Nakanishi T, Forgetta V, Handa T, Hirai T, Mooser V, Lathrop GM, Cookson WOCM, Richards JBet al., 2020, The undiagnosed disease burden associated with alpha-1 antitrypsin deficiency genotypes, European Respiratory Journal, Vol: 56, Pages: 1-11, ISSN: 0903-1936

Alpha-1 antitrypsin deficiency (AATD), mainly due to the PI*ZZ genotype in SERPINA1, is one of the most common inherited diseases. Since it is associated with a high disease burden and partially prevented by smoking cessation, identification of PI*ZZ individuals through genotyping could improve health outcomes.We examined the frequency of the PI*ZZ genotype in individuals with and without diagnosed AATD from UK Biobank, and assessed the associations of the genotypes with clinical outcomes and mortality. A phenome-wide association study (PheWAS) was conducted to reveal disease associations with genotypes. A polygenic risk score (PRS) for forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio was used to evaluate variable penetrance of PI*ZZ.Among 458 164 European-ancestry participants in UK Biobank, 140 had the PI*ZZ genotype and only nine (6.4%, 95% CI 3.4–11.7%) of them were diagnosed with AATD. Those with PI*ZZ had a substantially higher odds of COPD (OR 8.8, 95% CI 5.8–13.3), asthma (OR 2.0, 95% CI 1.4–3.0), bronchiectasis (OR 7.3, 95%CI 3.2–16.8), pneumonia (OR 2.7, 95% CI 1.5–4.9) and cirrhosis (OR 7.8, 95% CI 2.5–24.6) diagnoses and a higher hazard of mortality (2.4, 95% CI 1.2–4.6), compared to PI*MM (wildtype) (n=398 424). These associations were stronger among smokers. PheWAS demonstrated associations with increased odds of empyema, pneumothorax, cachexia, polycythaemia, aneurysm and pancreatitis. Polygenic risk score and PI*ZZ were independently associated with FEV1/FVC <0.7 (OR 1.4 per 1-sd change, 95% CI 1.4–1.5 and OR 4.5, 95% CI 3.0–6.9, respectively).The important underdiagnosis of AATD, whose outcomes are partially preventable through smoking cession, could be improved through genotype-guided diagnosis.

Journal article

Zhang YZ, Brambilla C, Molyneaux PL, Rice A, Robertus JL, Jordan S, Lim E, Lang-Lazdunski L, Begum S, Dusmet M, Anikin V, Beddow E, Finch J, Asadi N, Popat S, Le Quesne J, Husain AN, Cookson WO, Moffatt MF, Nicholson AGet al., 2020, Presence of pleomorphic features but not growth patterns improves prognostic stratification of epithelioid malignant pleural mesothelioma by 2-tier nuclear grade, Histopathology, Vol: 77, Pages: 423-436, ISSN: 0309-0167

AIMS: Nuclear grade has been recently validated as a powerful prognostic tool in epithelioid malignant pleural mesothelioma (E-MPM). In other studies histological parameters including pleomorphic features and growth patterns were also shown to exert prognostic impact. The primary aims of our study are (1) externally validate the prognostic role of pleomorphic features in E-MPM and (2) investigate if evaluating growth pattern in addition to 2-tier nuclear grade improves prognostication. METHODS AND RESULTS: 614 consecutive cases of E-MPM from our institution over a period of 15 years were retrospectively reviewed, of which 51 showed pleomorphic features. E-MPM with pleomorphic features showed significantly worse overall survival compared those without (5.4 months vs 14.7 months). Tumours with predominantly micropapillary pattern showed the worst survival (6.2 months) followed by solid (10.5 months), microcystic (15.3 months), discohesive (16.1 months), trabecular (17.6 months) and tubulo-papillary (18.6 months). Sub-classification of growth patterns into high grade (solid, micropapillary) and low grade (all others) led to good separation of overall survival (10.5 months vs. 18.0 months) but did not predict survival independent of 2-tier nuclear grade. A composite score comprised of growth pattern and 2-tier nuclear grade did not improve prognostication compared with nuclear grade alone. Intra-tumoural heterogeneity in growth patterns is ubiquitous. CONCLUSIONS: Our findings support the incorporation of E-MPM with pleomorphic features in the epithelioid subtype as a highly aggressive variant distinct from 2-tier nuclear grade. E-MPM demonstrates extensive heterogeneity in growth pattern but its evaluation does not offer additional prognostic utility to 2-tier nuclear grade.

Journal article

Cookson WOCM, Moffatt MF, 2020, In the Wrong Place at the Wrong Time: Microbial Misplacement and Acute Respiratory Distress Syndrome, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 201, Pages: 506-507, ISSN: 1073-449X

Journal article

Zhang YZ, Brambilla C, Molyneaux PL, Rice A, Robertus JL, Jordan S, Lim E, Lang-Lazdunski L, Begum S, Dusmet M, Anikin V, Beddow E, Finch J, Asadi N, Popat S, Cookson WOC, Moffatt MF, Nicholson AGet al., 2020, Utility of nuclear grading system in epithelioid malignant pleural mesothelioma in biopsy-heavy setting, The American Journal of Surgical Pathology, Vol: 44, Pages: 347-356, ISSN: 0147-5185

Nuclear grading systems for epithelioid malignant pleural mesothelioma (MPM) have been proposed but it remains uncertain if they could be applied in a biopsy-heavy setting. Using the proposed system, we conducted an independent, external validation study using 563 consecutive cases of epithelioid MPM diagnosed at our institution between 2003 and 2017, of which 87% of patients underwent biopsies only. The median number of sites sampled was 1, with a median maximum tissue dimension of 17 mm (biopsy) and 150 mm (resection). The median overall survival (OS) was 14.7 months. The frequencies of grade I, II, and III tumors were 31% (132/563), 52% (292/563), and 17% (94/563). Grade I tumors were associated with the most favorable median OS (24.7 mo) followed by grades II (12.7 mo) and III (7.2 mo). The 2-tier nuclear grade separated tumors into low grade (19.3 mo) and high grade (8.9 mo). In multivariate analysis, 3-tier nuclear grade, 2-tier nuclear grade, and mitosis-necrosis score predicted OS independent of age, procedural type, solid-predominant growth pattern, necrosis, and atypical mitosis (all P<0.001 except 2-tier nuclear grade, P=0.001). In the scenario of a single- site biopsy with tissue dimension ≤10 mm, none but age (P=0.002) were independently predictive. Our data also suggested sampling 3 sites or a maximum tissue dimension of at least 20 mm from a single site is optimal for nuclear grade assessment. In conclusion our study confirmed the utility of nuclear grade in epithelioid MPM using a biopsy-heavy cohort provided the tissue sample met minimum dimensional criteria.

Journal article

Zhu Z, Guo Y, Shi H, Liu C-L, Panganiban RA, Chung W, O'Connor LJ, Himes BE, Gazal S, Hasegawa K, Camargo CA, Qi L, Moffatt MF, Hu FB, Lu Q, Cookson WOC, Liang Let al., 2020, Shared genetic and experimental links between obesity-related traits and asthma subtypes in UK Biobank, JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, Vol: 145, Pages: 537-549, ISSN: 0091-6749

Journal article

Nastase A, Mandal A, Lu SK, Anbunathan H, Morris-Rosendahl D, Zhang YZ, Sun X-M, Gennatas S, Rintoul RC, Edwards M, Bowman A, Chernova T, Benepal T, Lim E, Taylor AN, Nicholson AG, Popat S, Willis AE, MacFarlane M, Lathrop M, Bowcock AM, Moffatt MF, Cookson WOCMet al., 2020, Integrated genomics identify novel immunotherapy targets for malignant mesothelioma

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Malignant pleural mesothelioma (MPM) is an aggressive malignancy with limited effective therapies.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Previously unrecognised losses of <jats:italic>SUFU</jats:italic> locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including <jats:italic>VISTA</jats:italic>. Co-deletion of Interferon Type I genes and <jats:italic>CDKN2A</jats:italic> was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in <jats:italic>RB1</jats:italic> in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary MPM cells. Defects in Hippo pathways that included <jats:italic>RASSF7</jats:italic> amplification and <jats:italic>NF2</jats:italic> or <jats:italic>LATS1</jats:italic>/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Our results suggest new therapeutic avenues in MPM and provide targets and biomarkers for immunotherapy.</jats:p></jats:sec>

Journal article

Punjabi P, 2019, Discussion., American Association of Thoracic Surgery

Conference paper

Hoang LT, Domingo-Sabugo C, Starren ES, Willis-Owen SA, Morris-Rosendah DJ, Nicholson AG, Cookson WOCM, Moffatt MFet al., 2019, Metabolomic, transcriptomic and genetic integrative analysis reveals important roles of adenosine diphosphate in haemostasis and platelet activation in non-small-cell lung cancer, Molecular Oncology, Vol: 13, Pages: 2406-2421, ISSN: 1574-7891

Lung cancer is the leading cause of cancer‐related deaths in the world. The most prevalent subtype, accounting for 85% of cases, is non‐small‐cell lung cancer (NSCLC). Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) are the most common subtypes. Despite recent advances in treatment, the low 5‐year survival rate of NSCLC patients (approximately 13%) reflects the lack of early diagnostic biomarkers and incomplete understanding of the underlying disease mechanisms. We hypothesized that integration of metabolomic, transcriptomic and genetic profiles of tumours and matched normal tissues could help to identify important factors and potential therapeutic targets that contribute to tumorigenesis. We integrated omics profiles in tumours and matched adjacent normal tissues of patients with LUSC (N = 20) and LUAD (N = 17) using multiple system biology approaches. We confirmed the presence of previously described metabolic pathways in NSCLC, particularly those mediating the Warburg effect. In addition, through our combined omics analyses we found that metabolites and genes that contribute to haemostasis, angiogenesis, platelet activation and cell proliferation were predominant in both subtypes of NSCLC. The important roles of adenosine diphosphate in promoting cancer metastasis through platelet activation and angiogenesis suggest this metabolite could be a potential therapeutic target.

Journal article

Cuthbertson L, Oo SWC, Cox MJ, Khoo S-K, Cox DW, Chidlow G, Franks K, Prastanti F, Borland ML, Gern JE, Smith DW, Bizzintino JA, Laing IA, Le Souef PN, Moffatt MF, Cookson WOCet al., 2019, Viral respiratory infections and the oropharyngeal bacterial microbiota in acutely wheezing children, PLOS ONE, Vol: 14, ISSN: 1932-6203

Journal article

Sugier P-E, Sarnowski C, Granell R, Laprise C, Ege MJ, Margaritte-Jeannin P, Dizier M-H, Minelli C, Moffatt MF, Lathrop M, Cookson WOCM, Henderson AJ, von Mutius E, Kogevinas M, Demenais F, Bouzigon Eet al., 2019, Genome-wide interaction study of early-life smoking exposure on time-to-asthma onset in childhood, Clinical and Experimental Allergy, Vol: 49, Pages: 1342-1351, ISSN: 0954-7894

BACKGROUND: Asthma, a heterogeneous disease with variable age of onset, results from the interplay between genetic and environmental factors. Early-life tobacco smoke (ELTS) exposure is a major asthma risk factor. Only a few genetic loci have been reported to interact with ELTS exposure in asthma. OBJECTIVE: Our aim was to identify new loci interacting with ELTS exposure on time-to-asthma onset (TAO) in childhood. METHODS: We conducted genome-wide interaction analyses of ELTS exposure on time-to-asthma onset in childhood in five European-ancestry studies (totaling 8,273 subjects) using Cox proportional-hazard model. The results of all five genome-wide analyses were meta-analyzed. RESULTS: The 13q21 locus showed genome-wide significant interaction with ELTS exposure (P=4.3x10-8 for rs7334050 within KLHL1 with consistent results across the five studies). Suggestive interactions (P<5x10-6 ) were found at three other loci: 20p12 (rs13037508 within MACROD2; P=4.9x10-7 ), 14q22 (rs7493885 near NIN; P=2.9x10-6 ) and 2p22 (rs232542 near CYP1B1; P=4.1x10-6 ). Functional annotations and the literature showed that the lead SNPs at these four loci influence DNA methylation in the blood and are located nearby CpG sites reported to be associated with exposure to tobacco smoke components, which strongly support our findings. CONCLUSION AND CLINICAL RELEVANCE: We identified novel candidate genes interacting with ELTS exposure on time-to-asthma onset in childhood. These genes have plausible biological relevance related to tobacco smoke exposure. Further epigenetic and functional studies are needed to confirm these findings and to shed light on the underlying mechanisms. This article is protected by copyright. All rights reserved.

Journal article

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

Ciano M, Mantellato G, Connolly M, Paul-Clark M, Mitchell J, Wilson-Owen S, Cookson W, Moffatt M, Hughes S, Polkey M, Kemp P, Natanek Set al., 2019, EGF receptor (EGFR) inhibition promotes a slow-twitch oxidative, over a fast-twitch, muscle phenotype, Scientific Reports, Vol: 9, ISSN: 2045-2322

A low quadriceps slow-twitch (ST), oxidative (relative to fast-twitch) fiber proportion is prevalent in chronic diseases such Chronic Obstructive Pulmonary Disease (COPD) and is associated with exercise limitation and poor outcomes. Benefits of an increased ST fiber proportion are demonstrated in genetically modified animals. Pathway analysis of published data of differentially expressed genes in mouse ST and FT fibers, mining of our microarray data and a qPCR analysis of quadriceps specimens from COPD patients and controls were performed. ST markers were quantified in C2C12 myotubes with EGF-neutralizing antibody, EGFR inhibitor or an EGFR-silencing RNA added. A zebrafish egfra mutant was generated by genome editing and ST fibers counted. EGF signaling was (negatively) associated with the ST muscle phenotype in mice and humans, and muscle EGF transcript levels were raised in COPD. In C2C12 myotubes, EGFR inhibition/silencing increased ST, including mitochondrial, markers. In zebrafish, egfra depletion increased ST fibers and mitochondrial content. EGF is negatively associated with ST muscle phenotype in mice, healthy humans and COPD patients. EGFR blockade promotes the ST phenotype in myotubes and zebrafish embryos. EGF signaling suppresses the ST phenotype, therefore EGFR inhibitors may be potential treatments for COPD-related muscle ST fiber loss.

Journal article

Januszewski A, Zhang YZ, Chang W-C, Laggner U, Bowman A, Adefila-Ideozu T, Vivanco I, Moffatt MF, Cookson WO, Gupta NP, Nicholson AG, Bowcock A, Popat Set al., 2019, Impact of MET variants on PD-L1 expression in pleomorphic lung carcinoma, European Lung Cancer Congress (ELCC), Publisher: OXFORD UNIV PRESS, Pages: 1-1, ISSN: 0923-7534

Conference paper

Ahmed B, Cox M, Cuthbertson L, James P, Cookson W, Davies J, Moffatt M, Bush Aet al., 2019, Longitudinal development of the airway microbiota in infants with cystic fibrosis, Scientific Reports, Vol: 9, ISSN: 2045-2322

The pathogenesis of airway infection in cystic fibrosis (CF) is poorly understood. We performed a longitudinal study coupling clinical information with frequent sampling of the microbiota to identify changes in the airway microbiota in infancy that could underpin deterioration and potentially be targeted therapeutically. Thirty infants with CF diagnosed on newborn screening (NBS) were followed for up to two years. Two hundred and forty one throat swabs were collected as a surrogate for lower airway microbiota (median 35 days between study visits) in the largest longitudinal study of the CF oropharyngeal microbiota. Quantitative PCR and Illumina sequencing of the 16S rRNA bacterial gene were performed. Data analyses were conducted in QIIME and Phyloseq in R. Streptococcus spp. and Haemophilus spp. were the most common genera (55% and 12.5% of reads respectively) and were inversely related. Only beta (between sample) diversity changed with age (Bray Curtis r2 = 0.15, P = 0.03). Staphylococcus and Pseudomonas were rarely detected. These results suggest that Streptococcus spp. and Haemophilus spp., may play an important role in early CF. Whether they are protective against infection with more typical CF micro-organisms, or pathogenic and thus meriting treatment needs to be determined.

Journal article

Turek EM, Cox MJ, Hunter M, Hui J, James P, Willis-Owen SAG, Cuthbertson L, James A, Musk AW, Moffatt MF, Cookson WOCMet al., 2019, Smoking, asthma and airway microbial disruption, Publisher: Cold Spring Harbor Laboratory

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Normal airway microbial communities play a central role in respiratory health but are poorly characterized. Cigarette smoking is the dominant global environmental influence on lung function, and asthma has become the most prevalent chronic respiratory disease worldwide. Both conditions have major microbial components that are also poorly defined.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We investigated airway bacterial communities in a general population sample of 529 Australian adults. Posterior oropharyngeal swabs were analysed by sequencing of the 16S rRNA and methionine aminopeptidase genes. The microbiota were characterised according to their prevalence, abundance, and network memberships.</jats:p></jats:sec><jats:sec><jats:title>Findings</jats:title><jats:p>Microbial communities were similar across the population and were strongly organized into co-abundance networks. Smoking associated with diversity loss, negative effects on abundant taxa, profound alterations to network structure and expansion of <jats:italic>Streptococcus</jats:italic> spp. By contrast, the asthmatic microbiota were selectively affected by an increase in <jats:italic>Neisseria</jats:italic> spp. and by reduced numbers of low abundance but prevalent organisms.</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>Our study shows healthy airway microbiota are contained within a highly structured ecosystem, indicating balanced relationships between the microbiome and human host factors. The marked abnormalities in smokers may be pathogenic for chronic obstructive pulmonary disease (COPD) and lung cancer. The narrow spectrum of abnormalities in asthmatics encourages investigation of damaging and

Working paper

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

Wootton DG, Cox MJ, Gloor GB, Litt D, Hoschler K, German E, Court J, Eneje O, Keogan L, Macfarlane L, Wilks S, Diggles PJ, Woodhead M, Moffatt MF, Cookson WOC, Gordon SBet al., 2019, A haemophilus sp. dominates the microbiota of sputum from UK adults with non-severe community acquired pneumonia and chronic lung disease, Scientific Reports, Vol: 9, ISSN: 2045-2322

The demographics and comorbidities of patients with community acquired pneumonia (CAP) vary enormously but stratified treatment is difficult because aetiological studies have failed to comprehensively identify the pathogens. Our aim was to describe the bacterial microbiota of CAP and relate these to clinical characteristics in order to inform future trials of treatment stratified by co-morbidity. CAP patients were prospectively recruited at two UK hospitals. We used 16S rRNA gene sequencing to identify the dominant bacteria in sputum and compositional data analysis to determine associations with patient characteristics. We analysed sputum samples from 77 patients and found a Streptococcus sp. and a Haemophilus sp. were the most relatively abundant pathogens. The Haemophilus sp. was more likely to be dominant in patients with pre-existing lung disease, and its relative abundance was associated with qPCR levels of Haemophilus influenzae. The most abundant Streptococcus sp. was associated with qPCR levels of Streptococcus pneumoniae but dominance could not be predicted from clinical characteristics. These data suggest chronic lung disease influences the microbiota of sputum in patients with CAP. This finding could inform a trial of stratifying empirical CAP antibiotics to target Haemophilus spp. in addition to Streptococcus spp. in those with chronic lung disease.

Journal article

Zhang Y, Willis-Owen S, Spiegel S, Lloyd C, Moffatt M, Cookson Wet al., 2019, The ORMDL3 asthma gene regulates ICAM1 and has multiple effects on cellular inflammation, American Journal of Respiratory and Critical Care Medicine, Vol: 199, Pages: 478-488, ISSN: 1073-449X

Rationale: Polymorphisms on chromosome 17q21 confer the major genetic susceptibility to childhood-onset asthma. Risk alleles positively correlate with ORMDL3 expression. The locus influences disease severity and the frequency of human rhinovirus (HRV) initiated exacerbations. ORMDL3 is known to regulate sphingolipid synthesis by binding serine palmitoyltransferase (SPT), but its role in inflammation is incompletely understood. Objectives: To investigate the role of ORMDL3 in cellular inflammation. Methods: We modelled time-series of IL1B-induced inflammation in A549 cells, using cytokine production as outputs and testing effects of ORMDL3 siRNA knockdown, ORMDL3 overexpression, and the SPT inhibitor myriocin. We replicated selected findings in normal human bronchial epithelial (NHBE) cells. Cytokine and metabolite levels were analysed by ANOVA. Transcript abundances were analysed by group means parameterisation, controlling the false discovery rate (FDR) below 0.05. Measurements and Main Results: Silencing ORMDL3 led to steroid-independent reduction of IL6 and IL8 release and reduced ER stress after IL1B. Overexpression and myriocin conversely augmented cytokine release. Knockdown reduced expression of genes regulating host-pathogen interactions, stress responses and ubiquitination: in particular ORMDL3 knockdown strongly reduced expression of the HRV receptor ICAM1. Silencing led to changes in levels of transcripts and metabolites integral to glycolysis. Increased levels of ceramides and the immune mediator sphingosine-1-P (S1P) were also observed. Conclusions: The results show ORMDL3 has pleiotropic effects during cellular inflammation, consistent with its substantial genetic influence on childhood asthma. Actions on ICAM1 provide a mechanism for the locus to confer susceptibility to HRV-induced asthma.

Journal article

Januszewski A, Chang W, Zhang Y, Laggner U, Bowman A, Adefila-Ideozu T, Moffatt M, Cookson W, Nicholson A, Popat S, Bowcock Aet al., 2019, Intratumoral heterogeneity in PD-L1 expression in pleomorphic lung carcinoma: implications for management of stage III disease, British Thoracic Oncology Group, Publisher: Elsevier, ISSN: 0169-5002

Conference paper

Cowman SA, James P, Wilson R, Cookson WOC, Moffatt MF, Loebinger MRet al., 2018, Profiling mycobacterial communities in pulmonary nontuberculous mycobacterial disease, PLoS ONE, Vol: 13, ISSN: 1932-6203

The diagnosis of pulmonary non-tuberculous mycobacterial disease (pNTM) is dependent on the isolation of NTM in culture, which is prone to overgrowth and contamination and may not capture the diversity of mycobacteria present, including rare or unidentified species. This study aimed to develop a culture independent method of detecting and identifying mycobacteria from sputum samples using partial sequencing of the hsp65 gene. DNA was extracted from sputum samples from subjects with pNTM and disease controls. Multiplexed partial sequencing of the hsp65 gene was performed using the Illumina MiSeq and custom primers. A reference database of hsp65 sequences was created for taxonomy assignment. Sequencing results were obtained from 42 subjects (31 cases, 11 controls). Mycobacterial sequences were identified in all subjects. In 90.5% of samples more than one species was found (median 5.5). The species isolated in culture was detected by sequencing in 81% of subjects and was the most abundant species in 62%. The sequencing of NTM from clinical samples reveals a far greater diversity than conventional culture and suggests NTM are present as communities rather than a single species. NTM were found to be present even in the absence of isolation in culture or clinical disease.

Journal article

Garcia AD, Lidwien AMS, Bossers A, Inge MW, Schmitt H, Markus JE, Depner M, Mueller-Rompa S, Schmausser-Hechfellner E, Michael JC, Cookson W, Moffatt M, von Mutius E, Dick JHet al., 2018, Indoor airborne microbiota composition associated with asthma and atopy in rural children, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936

Conference paper

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

Willis-Owen SAG, Thompson AR, Kemp P, Moffatt MF, Polkey M, Cookson W, Natanek Set al., 2018, COPD is accompanied by co-ordinated transcriptional perturbation in the quadriceps affecting the mitochondria and extracellular matrix, Scientific Reports, Vol: 8, ISSN: 2045-2322

Skeletal muscle dysfunction is a frequent extra-pulmonary manifestation of Chronic Obstructive Pulmonary Disease (COPD) with implications for both quality of life and survival. The underlying biology nevertheless remains poorly understood. We measured global gene transcription in the quadriceps using Affymetrix HuGene1.1ST arrays in an unselected cohort of 79 stable COPD patients in secondary care and 16 healthy age- and gender-matched controls. We detected 1,826 transcripts showing COPD-related variation. Eighteen exhibited ≥2fold changes (SLC22A3, FAM184B, CDKN1A, FST, LINC01405, MUSK, PANX1, ANKRD1, C12orf75, MYH1, POSTN, FRZB, TNC, ACTC1, LINC00310, MYH3, MYBPH and AREG). Thirty-one transcripts possessed previous reported evidence of involvement in COPD through genome-wide association, including FAM13A. Network analysis revealed a substructure comprising 6 modules of co-expressed genes. We identified modules with mitochondrial and extracellular matrix features, of which IDH2, a central component of the mitochondrial antioxidant pathway, and ABI3BP, a proposed switch between proliferation and differentiation, represent hubs respectively. COPD is accompanied by coordinated patterns of transcription in the quadriceps involving the mitochondria and extracellular matrix and including genes previously implicated in primary disease processes.

Journal article

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