Imperial College London

PROFESSOR MIRIAM F. MOFFATT

Faculty of MedicineNational Heart & Lung Institute

Professor of Respiratory Genetics
 
 
 
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Contact

 

+44 (0)20 7594 2942m.moffatt

 
 
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Location

 

400Guy Scadding BuildingRoyal Brompton Campus

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Summary

 

Publications

Publication Type
Year
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299 results found

Davies J, Hughes D, Rosenthal M, Cuthbertson L, ramadan N, Felton I, Simmonds N, Loebinger M, price H, Armstrong-James D, elborn S, Cookson W, Moffatt Met al., 2022, An invisible threat? Aspergillus positive cultures and co-infecting bacteria in airway sample, Journal of Cystic Fibrosis, ISSN: 1569-1993

BackgroundAspergillus fumigatus (Af) infection is associated with poor lung health in chronic suppurative lung diseases but often goes undetected. We hypothesised that inhibition of Af growth by Pseudomonas aeruginosa (Pa) increases the frequency of false-negative Af culture in co-infected people. Using a substantial group of cystic fibrosis (CF) airway samples, we assessed the relationship between Af and bacterial pathogens, additionally comparing fungal culture with next-generation sequencing.MethodsFrequency of co-culture was assessed for 44,554 sputum/BAL cultures, from 1,367 CF patients between the years 2010–2020. In a subgroup, Internal Transcribed Spacer-2 (ITS2) fungal sequencing was used to determine sequencing-positive, culture-negative (S+/C-) rates.ResultsPa+ samples were nearly 40% less likely (P<0.0001) than Pa- samples to culture Af, an effect that was also seen with some other Gram-negative isolates. This impact varied with Pa density and appeared to be moderated by Staphylococcus aureus co-infection. Sequencing identified Af-S+/C- for 40.1% of tested sputa. Samples with Pa had higher rates of Af-S+/C- (49.3%) than those without (35.7%; RR 1.38 [1.02–1.93], P<0.05). Af-S+/C- rate was not changed by other common bacterial infections. Pa did not affect the S+/C- rates of Candida, Exophiala or Scedosporium.ConclusionsPa/ Af co-positive cultures are less common than expected in CF. Our findings suggest an Af-positive culture is less likely in the presence of Pa. Interpretation of negative cultures should be cautious, particularly in Pa-positive samples, and a companion molecular diagnostic could be useful. Further work investigating mechanisms, alternative detection techniques and other chronic suppurative lung diseases is needed.

Journal article

Shah A, Hull J, Moffatt M, Cookson W, Kelleher W, Cuthbertson Let al., 2022, Evidence of immunometabolic dysregulation and airway dysbiosis in athletes susceptible to respiratory illness, EBioMedicine, Vol: 79, Pages: 1-16, ISSN: 2352-3964

BackgroundRespiratory tract infection (RTI) is a leading cause of training and in-competition time-loss in athlete health. The immune factors associated with RTI susceptibility remain unclear. In this study, we prospectively characterise host immune factors in elite athletes exhibiting RTI susceptibility.MethodsPeripheral blood lymphocyte flow cytometry phenotyping and 16S rRNA microbial sequencing of oropharyngeal swabs was performed in a prospective elite athlete cohort study (n = 121). Mass cytometry, peripheral blood mononuclear cell (PBMC) stimulation and plasma metabolic profiling was performed in age-matched highly-susceptible (HS) athletes (≥4RTI in last 18 months) (n = 22) compared to non-susceptible (NS) (≤1RTI in last 18 months) (n = 23) athletes. Findings were compared to non-athletic healthy controls (HC) (n = 19).FindingsAthletes (n = 121) had a reduced peripheral blood memory T regulatory cell compartment compared to HC (p = 0.02 (95%CI:0.1,1.0)) and reduced upper airway bacterial biomass compared to HC (p = 0.032, effect size r = 0.19). HS athletes (n = 22) had lower circulating memory T regulatory cells compared to NS (n = 23) athletes (p = 0.005 (95%CI:-1.5,-0.15)) and HC (p = 0.002 (95%CI:-1.9,-0.3) with PBMC microbial stimulation assays revealing a T-helper 2 skewed immune response compared to HC. Plasma metabolomic profiling showed differences in sphingolipid pathway metabolites (a class of lipids important in infection and inflammation regulation) in HS compared to NS athletes and HC, with sphingomyelin predictive of RTI infection susceptibility (p = 0.005).InterpretationAthletes susceptible to RTI have reduced circulating memory T regulatory cells, metabolic dysregulation of the sphingolipid pathway and evidence of upper airway bacterial dysbiosis.FundingThis study was funded by the English Institute of Sport (UK).

Journal article

Hull RC, Huang JTJ, Barton AK, Keir HR, Ellis H, Cookson WOC, Moffatt MF, Loebinger MR, Chalmers JDet al., 2022, Sputum Proteomics in Nontuberculous Mycobacterial Lung Disease., Chest, Vol: 161, Pages: 1180-1191

BACKGROUND: Nontuberculous mycobacterial (NTM) infections are difficult to diagnose and treat. Biomarkers to identify patients with active infection or at risk of disease progression would have clinical utility. Sputum is the most frequently used matrix for the diagnosis of NTM lung disease. RESEARCH QUESTION: Can sputum proteomics be used to identify NTM-associated inflammatory profiles in sputum? STUDY DESIGN AND METHODS: Patients with NTM lung disease and a matched cohort of patients with COPD, bronchiectasis (BE), and cystic fibrosis (CF) without NTM lung disease were enrolled from two hospitals in the United Kingdom. Liquid chromatography-tandem mass spectrometry was used to identify proteomic biomarkers associated with underlying diagnosis (COPD, BE, and CF), the presence of NTM lung disease defined according to American Thoracic Society/Infectious Diseases Society of America criteria, and severity of NTM. A subset of patients receiving guideline-concordant NTM treatment were studied to identify protein changes associated with treatment response. RESULTS: This study analyzed 95 sputum samples from 55 subjects (BE, n = 21; COPD, n = 19; CF, n = 15). Underlying disease and infection with Pseudomonas aeruginosa were the strongest drivers of sputum protein profiles. Comparing protein abundance in COPD, BE, and CF found that 12 proteins were upregulated in CF compared with COPD, including MPO, AZU1, CTSG, CAT, and RNASE3, with 21 proteins downregulated, including SCGB1A1, IGFBP2, SFTPB, GC, and CFD. Across CF, BE, and COPD, NTM infection (n = 15) was not associated with statistically significant differences in sputum protein profiles compared with those without NTM. Two proteins associated with iron chelation were significantly downregulated in severe NTM disease. NTM treatment was associated with heterogeneous changes in the sputum protein profile. Patients with NTM and a decrease in immune response proteins had a subjective symptomatic improve

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., 2022, Integrated genomics point to immune vulnerabilities in pleural mesothelioma (vol 11, 19138, 2021), SCIENTIFIC REPORTS, Vol: 12, ISSN: 2045-2322

Journal article

Singanayagam A, Footitt J, Marczynski M, Radicioni G, Cross MT, Finney LJ, Trujillo-Torralbo M-B, Calderazzo MA, Zhu J, Aniscenko J, Clarke TB, Molyneaux PL, Bartlett NW, Moffatt MF, Cookson WO, Wedzicha JA, Evans CM, Boucher RC, Kesimer M, Lieleg O, Mallia P, Johnston SLet al., 2022, Airway mucins promote immunopathology in virus-exacerbated chronic obstructive pulmonary disease., Journal of Clinical Investigation, Vol: 132, Pages: 1-16, ISSN: 0021-9738

The respiratory tract surface is protected from inhaled pathogens by a secreted layer of mucus rich in mucin glycoproteins. Abnormal mucus accumulation is a cardinal feature of chronic respiratory diseases but the relationship between mucus and pathogens during exacerbations is poorly understood. We identified elevations in airway MUC5AC and MUC5B concentrations during spontaneous and experimentally-induced chronic obstructive pulmonary disease (COPD) exacerbations. MUC5AC was more sensitive to changes in expression during exacerbation and was therefore more predictably associated with virus load, inflammation, symptom severity, decrements in lung function, and secondary bacterial infections. MUC5AC was functionally related to inflammation as Muc5ac-deficient (Muc5ac-/-) mice had attenuated rhinovirus (RV)-induced airway inflammation and exogenous MUC5AC glycoprotein administration augmented inflammatory responses and increased release of extracellular adenosine triphosphate (ATP) in mice and human airway epithelial cell cultures. Hydrolysis of ATP suppressed MUC5AC augmentation of rhinovirus-induced inflammation in mice. Therapeutic suppression of mucin production using an epidermal growth factor receptor (EGFR) antagonist ameliorated immunopathology in a mouse COPD exacerbation model. The coordinated virus induction of MUC5AC and MUC5B suggests that non-Th2 mechanisms trigger mucin hypersecretion during exacerbations. Our data identifies a pro-inflammatory role for MUC5AC during viral infection and suggest that MUC5AC inhibition may ameliorate COPD exacerbations.

Journal article

Cookson W, Moffatt M, Rapeport G, Quint Jet al., 2022, A pandemic lesson for global lung diseases: exacerbations are preventable., American Journal of Respiratory and Critical Care Medicine, Vol: 205, Pages: 1271-1280, ISSN: 1073-449X

A dramatic global reduction in the incidence of common seasonal respiratory viral infections has resulted from measures to limit the transmission of SARS2-Cov-19 during the pandemic . This has been accompanied by falls reaching 50% internationally in the incidence of acute exacerbations of pre-existing chronic respiratory diseases that include asthma, Chronic Obstructive Pulmonary Disease (COPD) and Cystic Fibrosis (CF). At the same time, the incidence of acute bacterial pneumonia and sepsis has fallen steeply world-wide. Such findings demonstrate the profound impact of common respiratory viruses on the course of these global illnesses. Reduced transmission of common respiratory bacterial pathogens and their interactions with viruses appear also as central factors. This review summarises pandemic changes in exacerbation rates of asthma, COPD, Cystic Fibrosis (CF) and pneumonia. We draw attention to the substantial body of knowledge about respiratory virus infections in these conditions, and that it has not yet translated into clinical practice. Now the large-scale of benefits that could be gained by managing these pathogens is unmistakable, we suggest the field merits substantial academic and industrial investment. We consider how pandemic-inspired measures for prevention and treatment of common infections should become a cornerstone for managing respiratory diseases. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Journal article

White AD, Sibley L, Sarfas C, Morrison AL, Bewley K, Churchward C, Fotheringham S, Gkolfinos K, Gooch K, Handley A, Humphries HE, Hunter L, Kennard C, Longet S, Mabbutt A, Moffatt M, Rayner E, Tipton T, Watson R, Hall Y, Bodman-Smith M, Gleeson F, Dennis M, Salguero FJ, Carroll M, McShane H, Cookson W, Hopkin J, Sharpe Set al., 2022, Influence of Aerosol Delivered BCG Vaccination on Immunological and Disease Parameters Following SARS-CoV-2 Challenge in Rhesus Macaques, FRONTIERS IN IMMUNOLOGY, Vol: 12, ISSN: 1664-3224

Journal article

Cuthbertson L, James P, Habibi MS, Thwaites RS, Paras A, Chiu C, Openshaw PJM, Cookson WOC, Moffatt MFet al., 2022, Resilience of the respiratory microbiome in controlled adult RSV challenge study, European Respiratory Journal, Vol: 59, ISSN: 0903-1936

Journal article

Ahmed B, Cox MJ, Cuthbertson L, James P, Gardner L, Cookson W, Davies J, Moffatt M, Bush Aet al., 2021, Comparison of the airway microbiota in children with chronic suppurative lung disease, BMJ Open Respiratory Research, Vol: 8, Pages: 1-10, ISSN: 2052-4439

Rationale:The airway microbiota is important in chronic suppurative lung diseases (CSLD), such as primary ciliary dyskinesia (PCD) and cystic fibrosis (CF). This comparison has not previously been described but is important because difference between the two diseases may relate to the differing prognoses and lead to pathological insights and potentially, new treatments. Objectives:To compare the longitudinal development of the airway microbiota in children with PCD to that of CF and relate this to age and clinical status. Methods:Sixty-two age-matched children (age range 0.5–17 years) with PCD or CF (n=31 in each group) were recruited prospectively and followed for 1.1 years. Throat swabs or sputum as well as clinical information were collected at routine clinical appointments. 16S rRNA gene sequencing was performed. Measurements and Main Results:The microbiota was highly individual and more diverse in PCD and differed in community composition when compared with CF. Whilst Streptococcus was the most abundant genus in both conditions, Pseudomonas was more abundant in CF with Haemophilus more abundant in PCD (Padj=0.0005). In PCD only, an inverse relationship was seen in the relative abundance of Streptococcus and Haemophilus with age. Conclusions:Bacterial community composition differs between children with PCD and those with CF. Pseudomonas is more prevalent in CF and Haemophilus in PCD, at least until infection with Pseudomonas supervenes. Interactions between organisms, particularly members of Haemophilus, Streptococcus, and Pseudomonas genera appear important. Study of the interactions between these organisms may lead to new therapies or risk stratification.

Journal article

Cuthbertson L, Turner SEG, Jackson A, Ranson C, Loosemore M, Kelleher P, Cookson WOC, Moffatt MF, Hull JH, Shah Aet al., 2021, ELITE ATHLETES SUSCEPTIBLE TO RESPIRATORY TRACT INFECTION ARE CHARACTERISED BY REDUCED CIRCULATING MEMORY T REGULATORY CELLS, UPPER AIRWAY MICROBIAL DYSBIOSIS AND DYSREGULATION OF SPHINGOLIPID METABOLISM, Publisher: BMJ PUBLISHING GROUP, Pages: A61-A62, ISSN: 0040-6376

Conference paper

Zhu Z, Li J, Si J, Ma B, Shi H, Lv J, Cao W, Guo Y, Millwood IY, Walters RG, Lin K, Yang L, Chen Y, Du H, Yu B, Hasegawa K, Camargo CA, Moffatt MF, Cookson WOC, Chen J, Chen Z, Li L, Yu C, Liang Let al., 2021, A large-scale genome-wide association analysis of lung function in the Chinese population identifies novel loci and highlights shared genetic aetiology with obesity, European Respiratory Journal, Vol: 58, Pages: 1-16, ISSN: 0903-1936

Background Lung function is a heritable complex phenotype with obesity being one of its important risk factors. However, knowledge of their shared genetic basis is limited. Most genome-wide association studies (GWASs) for lung function have been based on European populations, limiting the generalisability across populations. Large-scale lung function GWASs in other populations are lacking.Methods We included 100 285 subjects from the China Kadoorie Biobank (CKB). To identify novel loci for lung function, single-trait GWAS analyses were performed on forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC in the CKB. We then performed genome-wide cross-trait analysis between lung function and obesity traits (body mass index (BMI), BMI-adjusted waist-to-hip ratio and BMI-adjusted waist circumference) to investigate the shared genetic effects in the CKB. Finally, polygenic risk scores (PRSs) of lung function were developed in the CKB and their interaction with BMI's association on lung function were examined. We also conducted cross-trait analysis in parallel with the CKB using up to 457 756 subjects from the UK Biobank (UKB) for replication and investigation of ancestry-specific effects.Results We identified nine genome-wide significant novel loci for FEV1, six for FVC and three for FEV1/FVC in the CKB. FEV1 and FVC showed significant negative genetic correlation with obesity traits in both the CKB and UKB. Genetic loci shared between lung function and obesity traits highlighted important biological pathways, including cell proliferation, embryo, skeletal and tissue development, and regulation of gene expression. Mendelian randomisation analysis suggested significant negative causal effects of BMI on FEV1 and on FVC in both the CKB and UKB. Lung function PRSs significantly modified the effect of change in BMI on change in lung function during an average follow-up of 8 years.Conclusion This large-scale GWAS of lung function identified novel loci

Journal article

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 M, Cookson Wet al., 2021, Integrated genomics point to immune vulnerabilities in pleural mesothelioma, Scientific Reports, Vol: 11, ISSN: 2045-2322

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

Journal article

Hull R, Huang JT-J, Dicker A, Keir HR, Ellis H, Cookson B, Moffatt M, Loebinger MR, Chalmers JDet al., 2021, Sputum proteomics of CF, BE and COPD with or without NTM infections, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936

Conference paper

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

Hughes DA, Cuthbertson L, Price H, Felton I, Coates M, Simmonds NJ, Loebinger MR, Armstrong-James D, Elborn JS, Cookson WO, Moffatt MF, Davies JCet al., 2021, PSEUDOMONAS AERUGINOSA IMPAIRS GROWTH OF ASPERGILLUS FROM CF AIRWAY SAMPLES, Publisher: BMJ PUBLISHING GROUP, Pages: A159-A159, ISSN: 0040-6376

Conference paper

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

Domingo-Sabugo C, Starren E, Mandal A, Nastase A, Hoang L, Edwards M, Morris-Rosendahl D, Lim E, Nicholson AG, Lathrop M, Cookson W, Moffatt Met al., 2020, Distinct Landscapes of Genomic Alterations between Lung Carcinoids and Non-Small Cell Lung Cancers, Publisher: SPRINGERNATURE, Pages: 528-528, ISSN: 1018-4813

Conference paper

Habibi M, Thwaites R, Chang M, Jozwik A, Paras A, Kirsebom F, Varese A, Owen A, Cuthbertson L, James P, Tunstall T, Nickle D, Hansel T, Moffatt M, Johansson C, Chiu C, Openshaw Pet al., 2020, Neutrophilic inflammation in the respiratory mucosa predisposes to RSV infection, Science, Vol: 370, Pages: 1-15, ISSN: 0036-8075

INTRODUCTIONEven with intimate exposure to a virus, some people fail to become infected. Variable transmission partly depends on the dose and duration of exposure but is also governed by the immune status of the host, such as the presence of specific protective antibodies or T cells. However, for some infections, the reasons for erratic transmission are largely unknown. For example, respiratory syncytial virus (RSV) can repeatedly reinfect individuals throughout their lives despite the presence of specific immunity. Additionally, antibodies and T cells have limited efficacy against newly emergent pathogens with pandemic potential. However, the intrinsic and innate mechanisms underlying protection when people are exposed to these viruses are poorly understood.RATIONALEWe reasoned that the prior state of the respiratory mucosa’s innate defenses may contribute to the variable outcome of RSV inoculation. By performing experimental challenge of adult volunteers, we were able to measure variations in the status of the nasal mucosa before inoculation and in mucosal responses during the presymptomatic phase of infection. Neither of these phases is easily observable during natural spontaneous transmission. Our observations could then be validated using specific interventional studies in a well-established mouse model of RSV infection.RESULTSAfter nasal administration of RSV, 57% of inoculated volunteers became infected. The uptake of infection was poorly explained by specific B or T cell immunity. However, transcriptomic profiling of the nasal tissue before inoculation demonstrated a neutrophilic inflammatory signal in those destined to develop symptomatic infection, and this was associated with suppression of an early interleukin-17 (IL-17)–dominated immune response during the presymptomatic period. This was followed by symptomatic infection associated with the expression of proinflammatory cytokines. By contrast, those who resisted infection showed a transient

Journal article

Hughes D, Cuthbertson L, Price H, Felton I, Coates M, Simmonds NJ, Loebinger M, Armstrong-James D, Elborn J, Cookson W, Moffatt M, Davies JCet al., 2020, PSEUDOMONAS AERUGINOSA IMPAIRS GROWTH OF ASPERGILLUS FROM CF AIRWAY SAMPLES, Publisher: WILEY, Pages: S153-S153, ISSN: 8755-6863

Conference paper

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

Groves HT, Higham SL, Moffatt MF, Cox MJ, Tregoning JSet al., 2020, Respiratory viral infection alters the gut microbiota by inducing inappetence, mBio, Vol: 11, ISSN: 2150-7511

Respiratory viral infections are extremely common, but their impacts on the composition and function of the gut microbiota are poorly understood. We previously observed a significant change in the gut microbiota after viral lung infection. Here, we show that weight loss during respiratory syncytial virus (RSV) or influenza virus infection was due to decreased food consumption, and that the fasting of mice altered gut microbiota composition independently of infection. While the acute phase tumor necrosis factor alpha (TNF-α) response drove early weight loss and inappetence during RSV infection, this was not sufficient to induce changes in the gut microbiota. However, the depletion of CD8+ cells increased food intake and prevented weight loss, resulting in a reversal of the gut microbiota changes normally observed during RSV infection. Viral infection also led to changes in the fecal gut metabolome, with a significant shift in lipid metabolism. Sphingolipids, polyunsaturated fatty acids (PUFAs), and the short-chain fatty acid (SCFA) valerate were all increased in abundance in the fecal metabolome following RSV infection. Whether this and the impact of infection-induced anorexia on the gut microbiota are part of a protective anti-inflammatory response during respiratory viral infections remains to be determined.

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

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

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