Publications

Journal article

Davies J, Mossop M, Jonathan I-H, Hughes D, Dobra R, Cunanan A, Rosenthal M, Carr S, Ramadan N, Nolan Let al., 2024,

Chronicity counts: the impact of P. aeruginosa, S. aureus, and co-infection in cystic fibrosis

, American Journal of Respiratory and Critical Care Medicine, Vol: 210, Pages: 240-242, ISSN: 1073-449X

Journal article

Wan Y, Myall AC, Boonyasiri A, Bolt F, Ledda A, Mookerjee S, Weisse AY, Getino M, Turton JF, Abbas H, Prakapaite R, Sabnis A, Abdolrasouli A, Malpartida-Cardenas K, Miglietta L, Donaldson H, Gilchrist M, Hopkins KL, Ellington MJ, Otter JA, Larrouy-Maumus G, Edwards AM, Rodriguez-Manzano J, Didelot X, Barahona M, Holmes AH, Jauneikaite E, Davies Fet al., 2024,

Integrated analysis of patient networks and plasmid genomes reveals a regional, multi-species outbreak of carbapenemase-producing Enterobacterales carrying both blaIMP and mcr-9 genes

, Journal of Infectious Diseases, Vol: 230, Pages: e159-e170, ISSN: 0022-1899

BackgroundCarbapenemase-producing Enterobacterales (CPE) are challenging in healthcare, with resistance to multiple classes of antibiotics. This study describes the emergence of imipenemase (IMP)–encoding CPE among diverse Enterobacterales species between 2016 and 2019 across a London regional network.MethodsWe performed a network analysis of patient pathways, using electronic health records, to identify contacts between IMP-encoding CPE–positive patients. Genomes of IMP-encoding CPE isolates were overlaid with patient contacts to imply potential transmission events.ResultsGenomic analysis of 84 Enterobacterales isolates revealed diverse species (predominantly Klebsiella spp, Enterobacter spp, and Escherichia coli); 86% (72 of 84) harbored an IncHI2 plasmid carrying blaIMP and colistin resistance gene mcr-9 (68 of 72). Phylogenetic analysis of IncHI2 plasmids identified 3 lineages showing significant association with patient contacts and movements between 4 hospital sites and across medical specialties, which was missed in initial investigations.ConclusionsCombined, our patient network and plasmid analyses demonstrate an interspecies, plasmid-mediated outbreak of blaIMPCPE, which remained unidentified during standard investigations. With DNA sequencing and multimodal data incorporation, the outbreak investigation approach proposed here provides a framework for real-time identification of key factors causing pathogen spread. Plasmid-level outbreak analysis reveals that resistance spread may be wider than suspected, allowing more interventions to stop transmission within hospital networks.SummaryThis was an investigation, using integrated pathway networks and genomics methods, of the emergence of imipenemase-encoding carbapenemase-producing Enterobacterales among diverse Enterobacterales species between 2016 and 2019 in patients across a London regional hospital network, which was missed on routine investigations.

Journal article

Katsoulis O, Toussaint M, Jackson M, Mallia P, Footitt J, Mincham K, Meyer G, Kebadze T, Gilmour A, Long M, Aswani A, Snelgrove R, Johnston S, Chalmers J, Singanayagam Aet al., 2024,

Neutrophil extracellular traps promote immunopathogenesis of virus-induced COPD exacerbations

, Nature Communications, Vol: 15, ISSN: 2041-1723

Respiratory viruses are a major trigger of exacerbations in chronic obstructive pulmonary disease (COPD). Airway neutrophilia is a hallmark feature of stable and exacerbated COPD but roles played by neutrophil extracellular traps (NETS) in driving disease pathogenesis are unclear. Here, using human studies of experimentally-induced and naturally-occurring exacerbations we identify that rhinovirus infection induces airway NET formation which is amplified in COPD and correlates with magnitude of inflammation and clinical exacerbation severity. We show that inhibiting NETosis protects mice from immunopathology in a model of virus-exacerbated COPD. NETs drive inflammation during exacerbations through release of double stranded DNA (dsDNA) and administration of DNAse in mice has similar protective effects. Thus, NETosis, through release of dsDNA, has a functional role in the pathogenesis of COPD exacerbations. These studies open up the potential for therapeutic targeting of NETs or dsDNA as a strategy for treating virus-exacerbated COPD.

Journal article

Koreshkov M, Takatsuna Y, Bismarck A, Fritz I, Reimhult E, Zirbs Ret al., 2024,

Sustainable food packaging using modified kombucha-derived bacterial cellulose nanofillers in biodegradable polymers

, RSC Sustainability, Vol: 2, Pages: 2367-2376

Incorporating nanoscale filler materials into polymers usually enhances mechanical properties, alters barrier characteristics, and enhances the visual appeal of consumer polymers. The growing recognition of the imperative to shift away from fossil-based, non-biodegradable polymers in single-use plastics and packaging materials toward fully renewable, recyclable, and/or biodegradable alternatives like PLA or PHBV has underscored the urgent need for the development of new, cost-effective, and scalable filler materials. Here, we demonstrate that the utilization of simple oligo-lactic acid modified bacterial cellulose (OLLA-g-BC) enhances the overall properties of commercial PLA and PHBV to a degree where it can directly compete with established conventional food packaging polymers. The key factor driving this enhancement lies in the uniform dispersion of the nanofiller throughout the bulk polymer, as visualized and confirmed through innovative 3D serial block face SEM analysis. The addition of 5% OLLA-g-BC increased the biodegradation rate of the nanocomposites without compromising their mechanical performance, leading to a ∼12% increase in Young's modulus for PLLA and a ∼14% decrease for PHBV. Filler incorporation resulted in a ∼23% and ∼45% decrease in oxygen permeability for PLLA and PHBV, respectively, while a ∼12% increase in water vapor permeability was observed for PLLA. Intensive investigations into the performance of nanocomposites clearly indicate that OLLA-grafted bacterial cellulose compound materials could significantly contribute to the realization of a fully circular, zero-waste economy.

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Journal article

Park Y-K, Sellés Vidal L, Bell D, Zabret J, Soldat M, Kavšček M, Ledesma-Amaro Ret al., 2024,

Efficient synthesis of limonene production in Yarrowia lipolytica by combinatorial engineering strategies

, Biotechnology for Biofuels and Bioproducts, Vol: 17, ISSN: 2731-3654

BackgroundLimonene has a variety of applications in the foods, cosmetics, pharmaceuticals, biomaterials, and biofuels industries. In order to meet the growing demand for sustainable production of limonene at industry scale, it is essential to find an alternative production system to traditional plant extraction. A promising and eco-friendly alternative is the use of microbes as cell factories for the synthesis of limonene.ResultsIn this study, the oleaginous yeast Yarrowia lipolytica has been engineered to produce D- and L-limonene. Four target genes, L- or D-LS (limonene synthase), HMG (HMG-CoA reductase), ERG20 (geranyl diphosphate synthase), and NDPS1 (neryl diphosphate) were expressed individually or fused together to find the optimal combination for higher limonene production. The strain expressing HMGR and the fusion protein ERG20-LS was the best limonene producer and, therefore, selected for further improvement. By increasing the expression of target genes and optimizing initial OD, 29.4 mg/L of L-limonene and 24.8 mg/L of D-limonene were obtained. We also studied whether peroxisomal compartmentalization of the synthesis pathway was beneficial for limonene production. The introduction of D-LS and ERG20 within the peroxisome improved limonene titers over cytosolic expression. Then, the entire MVA pathway was targeted to the peroxisome to improve precursor supply, which increased D-limonene production to 47.8 mg/L. Finally, through the optimization of fermentation conditions, D-limonene production titer reached 69.3 mg/L.ConclusionsIn this work, Y. lipolytica was successfully engineered to produce limonene. Our results showed that higher production of limonene was achieved when the synthesis pathway was targeted to the peroxisome, which indicates that this organelle can favor the bioproduction of terpenes in yeasts. This study opens new avenues for the efficient synthesis of valuable monoterpenes in Y. lipolytica.

Journal article

Mac Aogáin M, Xaverius Ivan F, Jaggi TK, Richardson H, Shoemark A, Narayana JK, Dicker AJ, Koh MS, Lee KCH, Thun How O, Poh ME, Chin KK, Hou ALY, Ser Hon P, Low TB, Abisheganaden JA, Dimakou K, Digalaki A, Kosti C, Gkousiou A, Hansbro PM, Blasi F, Aliberti S, Chalmers JD, Chotirmall SHet al., 2024,

Airway "Resistotypes" and Clinical Outcomes in Bronchiectasis.

, Am J Respir Crit Care Med, Vol: 210, Pages: 47-62

Rationale: Chronic infection and inflammation shapes the airway microbiome in bronchiectasis. Utilizing whole-genome shotgun metagenomics to analyze the airway resistome provides insight into interplay between microbes, resistance genes, and clinical outcomes. Objectives: To apply whole-genome shotgun metagenomics to the airway microbiome in bronchiectasis to highlight a diverse pool of antimicrobial resistance genes: the "resistome," the clinical significance of which remains unclear. Methods: Individuals with bronchiectasis were prospectively recruited into cross-sectional and longitudinal cohorts (n = 280), including the international multicenter cross-sectional Cohort of Asian and Matched European Bronchiectasis 2 (CAMEB 2) study (n = 251) and two independent cohorts, one describing patients experiencing acute exacerbation and a further cohort of patients undergoing Pseudomonas aeruginosa eradication treatment. Sputum was subjected to metagenomic sequencing, and the bronchiectasis resistome was evaluated in association with clinical outcomes and underlying host microbiomes. Measurements and Main Results: The bronchiectasis resistome features a unique resistance gene profile and increased counts of aminoglycoside, bicyclomycin, phenicol, triclosan, and multidrug resistance genes. Longitudinally, it exhibits within-patient stability over time and during exacerbations despite between-patient heterogeneity. Proportional differences in baseline resistome profiles, including increased macrolide and multidrug resistance genes, associate with shorter intervals to the next exacerbation, whereas distinct resistome archetypes associate with frequent exacerbations, poorer lung function, geographic origin, and the host microbiome. Unsupervised analysis of resistome profiles identified two clinically relevant "resistotypes," RT1 and RT2, the latter characterized by poor clinical outcomes, increased multidrug resistance, and P. a

Journal article

Chotirmall SH, Chalmers JD, 2024,

The Precision Medicine Era of Bronchiectasis.

, Am J Respir Crit Care Med, Vol: 210, Pages: 24-34

Journal article

Shteinberg M, Waterer G, Chotirmall SH, 2024,

A Global Effort to Stop the Vicious Vortex: A Special American Journal of Respiratory and Critical Care Medicine Issue for World Bronchiectasis Day 2024.

, Am J Respir Crit Care Med, Vol: 210, Pages: 1-3

Journal article

Kreuter M, Lee JS, Tzouvelekis A, Oldham JM, Molyneaux PL, Weycker D, Atwood M, Samara K, Kirchgässler K-U, Maher TMet al., 2024,

Modified blood cell GAP model as a prognostic biomarker in idiopathic pulmonary fibrosis

, ERJ Open Research, Vol: 10, ISSN: 2312-0541

BACKGROUND: The Gender, Age and Physiology (GAP) model is a simple mortality prediction tool in patients with idiopathic pulmonary fibrosis that uses demographic and physiological variables available at initial evaluation. White blood cell variables may have associations with idiopathic pulmonary fibrosis outcomes. We evaluated whether incorporating blood cell counts in modified GAP (cGAP) models would improve outcome prediction in patients with idiopathic pulmonary fibrosis. PATIENTS AND METHODS: This retrospective analysis included pooled data from phase 3 randomised trials of pirfenidone in idiopathic pulmonary fibrosis (ASCEND, CAPACITY 004, CAPACITY 006). Study outcomes (disease progression, all-cause mortality, all-cause hospitalisation, respiratory-related hospitalisation) were evaluated during the initial 1-year period. Shared frailty models were used to evaluate associations between continuous and categorical baseline white and red blood cell parameters and study outcomes in a bivariate context, and to evaluate the impact of adding continuous monocyte count (cGAP1) or white and red blood cell parameters (cGAP2) to traditional GAP variables in a multivariable context based on C-statistics changes. RESULTS: Data were pooled from 1247 patients (pirfenidone, n=623; placebo, n=624). Significant associations (bivariate analyses) were idiopathic pulmonary fibrosis progression with neutrophil and eosinophil counts; all-cause mortality with monocyte and neutrophil counts; all-cause hospitalisation with monocyte count, neutrophil count and haemoglobin level; and respiratory-related hospitalisation with monocyte count, neutrophil count and haemoglobin level. In multivariate analyses, C-statistics were highest for the cGAP2 model for each of the outcomes. CONCLUSION: Modified GAP models incorporating monocyte counts alone or plus other white and red blood cell variables may be useful to improve prediction of outcomes in patients with idiopathic pulmonary fibrosis.

Journal article

Patel S, Sylvester KP, Wu Z, Rhamie S, Dickel P, Maher TM, Molyneaux PL, Calverley PMA, Man WD-Cet al., 2024,

A comparison of respiratory oscillometry and spirometry in idiopathic pulmonary fibrosis: performance time, symptom burden and test-retest reliability.

, ERJ Open Res, Vol: 10, ISSN: 2312-0541

STUDY QUESTION: In large multinational patient surveys, spirometry (which requires repeated, reproducible maximal efforts) can be associated with cough, breathlessness and tiredness, particularly in those with idiopathic pulmonary fibrosis (IPF). Oscillometry is an effort-independent test of airways resistance and reactance. We hypothesised that oscillometry would take less time to perform and would be associated with reduced symptom burden than spirometry. PATIENTS AND METHODS: Spirometry and oscillometry were performed in 66 participants with IPF and repeated 2 weeks later. We compared time taken to perform tests, symptom burden and test-retest reliability with Bland-Altman plots and intraclass correlation coefficients (ICCs). RESULTS: Oscillometry took significantly less time to perform than spirometry (mean -4.5 (99% CI -6.0 to -3.0) min) and was associated with lower symptom burden scores for cough (-1.3, 99% CI -1.7 to -0.8), breathlessness (-1.0, 99% CI -1.4 to -0.5), and tiredness (-0.5, 99% CI -0.9 to -0.2). On Bland-Altman analysis, all measures showed good agreement, with narrow limits of agreement and the mean bias lying close to 0 in all cases. The ICCs for forced expiratory volume in 1 s and forced vital capacity were 0.94 and 0.89, respectively, and ranged between 0.70 and 0.90 for oscillometry measures. CONCLUSION: Oscillometry is quicker to perform and provokes less symptoms than spirometry in patients with IPF.

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