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Journal articleFarne H, Glanville N, Johnson N, et al., 2022,
Effect of CRTH2 antagonism on the response to experimental rhinovirus infection in asthma: a pilot randomized controlled trial
, Thorax, Vol: 77, Pages: 950-959, ISSN: 0040-6376Background and aimsThe CRTH2 antagonist timapiprant improved lung function and asthma control in a phase 2 study, with evidence suggesting reduced exacerbations. We aimed to assess whether timapiprant attenuated or prevented asthma exacerbations induced by experimental rhinovirus (RV) infection. We furthermore hypothesized that timapiprant would dampen RV-induced type 2 inflammation and consequently improve antiviral immune responses.MethodsAtopic patients with partially controlled asthma on maintenance inhaled corticosteroids were randomized to timapiprant (n=22) or placebo (n=22) and challenged with RV-A16 three weeks later. The primary endpoint was the cumulative lower respiratory symptom score over the 14 days post-infection. Upper respiratory symptoms, spirometry, airway hyperresponsiveness, exhaled nitric oxide, RV-A16 virus load and soluble mediators in upper and lower airways samples, and CRTH2 staining in bronchial biopsies were additionally assessed before and during RV-A16 infection.ResultsSix subjects discontinued the study and eight were not infected; outcomes were assessed in 16 timapiprant- and 14 placebo-treated, successfully infected subjects. There were no differences between treatment groups in clinical exacerbation severity including cumulative lower respiratory symptom score day 0-14 (difference 3.0 (95% CI -29.0 to 17.0), P=0.78), virus load, antiviral immune responses, or RV-A16-induced airway inflammation other than in the bronchial biopsies, where CRTH2 staining was increased during RV-A16 infection in the placebo- but not the timapiprant-treated group. Timapiprant had a favourable safety profile, with no deaths, serious adverse events, or drug-related withdrawals.ConclusionTimapiprant treatment had little impact on the clinicopathological changes induced by RV-A16 infection in partially controlled asthma.
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Journal articleLi L, Mac Aogáin M, Xu T, et al., 2022,
Neisseria species as pathobionts in bronchiectasis.
, Cell Host Microbe, Vol: 30, Pages: 1311-1327.e8Neisseria species are frequently identified in the bronchiectasis microbiome, but they are regarded as respiratory commensals. Using a combination of human cohorts, next-generation sequencing, systems biology, and animal models, we show that bronchiectasis bacteriomes defined by the presence of Neisseria spp. associate with poor clinical outcomes, including exacerbations. Neisseria subflava cultivated from bronchiectasis patients promotes the loss of epithelial integrity and inflammation in primary epithelial cells. In vivo animal models of Neisseria subflava infection and metabolipidome analysis highlight immunoinflammatory functional gene clusters and provide evidence for pulmonary inflammation. The murine metabolipidomic data were validated with human Neisseria-dominant bronchiectasis samples and compared with disease in which Pseudomonas-, an established bronchiectasis pathogen, is dominant. Metagenomic surveillance of Neisseria across various respiratory disorders reveals broader importance, and the assessment of the home environment in bronchiectasis implies potential environmental sources of exposure. Thus, we identify Neisseria species as pathobionts in bronchiectasis, allowing for improved risk stratification in this high-risk group.
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Journal articleKuhn T, Buffi M, Bindschedler S, et al., 2022,
Design and construction of 3D printed devices to investigate active and passive bacterial dispersal on hydrated surfaces
, BMC Biology, Vol: 20, ISSN: 1741-7007BackgroundTo disperse in water-unsaturated environments, such as the soil, bacteria rely on the availability and structure of water films forming on biotic and abiotic surfaces, and, especially, along fungal mycelia. Dispersal along such “fungal highways” may be driven both by mycelial physical properties and by interactions between bacteria and fungi. However, we still do not have a way to disentangle the biotic and abiotic elements.ResultsWe designed and 3D printed two devices establishing stable liquid films that support bacteria dispersal in the absence of biotic interactions. The thickness of the liquid film determined the presence of hydraulic flow capable of transporting non-motile cells. In the absence of flow, only motile cells can disperse in the presence of an energy source. Non-motile cells could not disperse autonomously without flow but dispersed as “hitchhikers” when co-inoculated with motile cells.ConclusionsThe 3D printed devices can be used as an abiotic control to study bacterial dispersal on hydrated surfaces, such as plant roots and fungal hyphae networks in the soil. By teasing apart the abiotic and biotic dimensions, these 3D printed devices will stimulate further research on microbial dispersal in soil and other water-unsaturated environments.
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Journal articleKotta-Loizou I, 2022,
Molecular origins of transcriptional heterogeneity in diazotrophic Klebsiella oxytoca
, mSystems, Vol: 7, Pages: 1-13, ISSN: 2379-5077Phenotypic heterogeneity in clonal bacterial batch cultures has been shown for a range of bacterial systems; however, the molecular origins of such heterogeneity and its magnitude are not well understood. Under conditions of extreme low-nitrogen stress in the model diazotroph Klebsiella oxytoca, we found remarkably high heterogeneity of nifHDK gene expression, which codes for the structural genes of nitrogenase, one key enzyme of the global nitrogen cycle. This heterogeneity limited the bulk observed nitrogen-fixing capacity of the population. Using dual-probe, single-cell RNA fluorescent in situ hybridization, we correlated nifHDK expression with that of nifLA and glnK-amtB, which code for the main upstream regulatory components. Through stochastic transcription models and mutual information analysis, we revealed likely molecular origins for heterogeneity in nitrogenase expression. In the wild type and regulatory variants, we found that nifHDK transcription was inherently bursty, but we established that noise propagation through signaling was also significant. The regulatory gene glnK had the highest discernible effect on nifHDK variance, while noise from factors outside the regulatory pathway were negligible. Understanding the basis of inherent heterogeneity of nitrogenase expression and its origins can inform biotechnology strategies seeking to enhance biological nitrogen fixation. Finally, we speculate on potential benefits of diazotrophic heterogeneity in natural soil environments.
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Journal articleLu Y, Li F, Bai J, et al., 2022,
Rapid screening of antimicrobial probiotics using CRISPR cascade
, Biosensors and Bioelectronics, Vol: 216, Pages: 1-8, ISSN: 0956-5663Animal bacterial infection is increasingly threatening human health. Here we report a nucleic acid amplification-free CRISPR genetic assay that allows to rapidly screen potential food-origin antimicrobial probiotics. The assay (termed CRISPRzyme assay) is based on a CRISPR-DNAzyme cascade, where the target gene sequentially activated Cas12a protein and DNAzyme, yielding a limit of detection of 62 CFU Vibrio parahaemolyticus, 86 CFU Salmonella Typhimurium, and 82 CFU Listeria monocytogenes. The elimination of nucleic acid amplification shortens processing time and operational complexity. The assay was used to rapidly screen antimicrobial probiotics by end-measurement of fluorescence of pathogenic bacteria. Particularly, it can estimate the in vivo antimicrobial effect due to its capacity for pathogen quantification in complex samples. We found that isolates of Bacillus and lactic acid bacteria separated from fermented food exhibited strong antimicrobial activity for fish pathogen, Vibrio parahaemolyticus, and identified surfactin as the key antimicrobial component. The CRISPRzyme assay could ease antimicrobial probiotics screening, and constitutes a new tool for combatting pathogenic bacterial contamination and infection.
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Conference paperWiqvist K, Ingelsten M, Jevnikar Z, et al., 2022,
A transcriptomic, metabolic and phenotypic study of the anti-fibrotic effects of PGE2 in IPF lung fibroblasts and macrophages
, International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936 -
Conference paperMeldrum OW, Donaldson GC, Tiew PY, et al., 2022,
Integrated microbiome-mucus profiling in chronic obstructive pulmonary disease (COPD)
, International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936- Cite
- Citations: 1
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Conference paperLi L, Mac Aogain M, Xu T, et al., 2022,
Neisseria species as pathobionts in bronchiectasis
, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936 -
Conference paperStock C, Seeliger B, Cameli P, et al., 2022,
Extensive autoantibody panel in Systemic sclerosis associated Interstitial Lung Disease
, International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936- Cite
- Citations: 1
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Conference paperKreuter M, Lee JS, Tzouvelekis A, et al., 2022,
A modified blood cell GAP (cGAP) to prognosticate outcomes in IPF
, International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936- Cite
- Citations: 1
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