Biology subjects

Cookson, W. O.

Publications and source records attributed to Cookson, W. O..

5 recordsLinked to original sources

bioRxiv2024

Microbiome diversity, intra-mucosal bacteria and immune integration within normal and asthmatic airway mucosa

Asthma is characterized by reduced bronchial bacterial diversity and airway mucosal disruption. We examined spatial distributions of microbial sequences and host mucosal transcripts in bronchial biopsies from healthy controls and adult asthmatics. Bacteria were discovered by 16S ribosomal RNA staining in the lamina propria of all biopsies, with counts positively associated to lumenal bacterial diversity. Weighted correlation network analysis identified fifteen co-expression networks, including distinct programs of adaptive and innate immunity in differing spatial distributions. Stromal bacterial counts correlated significantly with eight of the network eigenvectors in directions compatible with beneficial relationships. The results suggest that dysbiosis may affect mucosal immunity through impaired interactions beneath the epithelial border. Intra-mucosal companion bacteria may be a potential substrate for selective management of immunity in a wide range of diseases. One-Sentence SummaryThe lung microbiome extends within the airway mucosa and associates spatially and functionally with immune networks.

microbiology↗

bioRxiv2022

Machine learning for exploring microbial inter-kingdom associations in Cystic Fibrosis and Bronchiectasis

BackgroundCystic fibrosis (CF) and non-CF bronchiectasis (BX) are characterised by severe chronic infections. Fungal and bacterial components of infection are both recognized. Little however is known about how fungal and bacterial organisms interact and whether these interactions impact on disease outcomes. MethodsQuantitative PCR and next-generation sequencing of ITS2 and 16S rRNA gene was carried out on 107 patients with CF or BX with clinically defined fungal infection status for all patients. The relationship between fungal and bacterial community composition was extensively explored using: random forest modelling, correlation network analysis, multi-omics factor analysis, and sample-wise clustering, to understand associations both within and between the microbial communities and their relationship to respiratory disease. ResultsRandom forest modelling demonstrated distinct fungal and bacterial communities within CF and BX patients. The inclusion of both kingdoms in the models did not improve discrimination between the two diseases. Within the CF patients, bacterial community composition was independent of clinical fungal disease status. Bacterial and fungal communities did not relate to the presence of CF pulmonary exacerbations (CFPE). Correlation network analysis found intra-kingdom interactions were predominant in the data. Multi-omics factor analysis (MOFA) revealed latent factors corresponding to single kingdoms. Thus, in the bacterial community we identified two distinct clusters characterised by the presence or absence of Pseudomonas-domination. This was independent of fungal community which was characterised by a second set of independent clusters dominated by Saccharomycetes. ConclusionsIn this study we were unable to detect clear evidence of clinically significant inter-kingdom interactions between the bacterial and fungal communities. While further work is required to fully understand microbial interaction within the lung, our data suggests that interkingdom interactions may not be the primary driver of patient outcomes, particularly in the context of fungal infection.

molecular biology↗

bioRxiv2019

MUC5AC drives COPD exacerbation severity through amplification of virus-induced airway inflammation

The respiratory tract surface is protected from inhaled pathogens by a secreted layer of mucus that is rich in mucin glycoproteins. Disrupted mucus production is a cardinal feature of chronic respiratory diseases but how this alteration affect interactions between mucins and pathogens is complex and poorly understood. Here, we identify a central and unexpected role for the major airway mucin MUC5AC in pathogenesis of virus-induced exacerbations of chronic obstructive pulmonary disease (COPD). Virus induction of MUC5AC is augmented in COPD compared to healthy subjects, is enhanced in frequent exacerbators and correlates with inflammation, symptom severity and secondary bacterial infection during exacerbation. MUC5AC is functionally related to inflammation as MUC5AC-deficient (Muc5ac-/-) mice had attenuated rhinovirus-induced airway inflammation whilst exogenous MUC5AC glycoprotein administration augmented virus-induced inflammatory responses and bacterial load. Mechanistically, MUC5AC-augmentation of rhinovirus-induced inflammation occurred through release of extracellular adenosine triphosphate (ATP). Therapeutic suppression of virus-induced MUC5AC release using an epidermal growth factor receptor (EGFR) inhibitor ameliorated exaggerated pro-inflammatory responses in a mouse COPD exacerbation model. Collectively, these studies demonstrate previously unrecognised pro-inflammatory effects of MUC5AC during infection and thus highlight a key unforeseen role in driving COPD exacerbation severity.

immunology↗

bioRxiv2019

Distinctive airway microbial ecology of smokers and asthmatics

BackgroundNormal 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. MethodsWe 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. FindingsMicrobial 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 Streptococcus spp. By contrast, the asthmatic microbiota were selectively affected by an increase in Neisseria spp. and by reduced numbers of low abundance but prevalent organisms. InterpretationOur 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 protective effects of specific bacteria. FundingThe study was funded by the Asmarley Trust and a Wellcome Senior Investigator Award to WOCC and MFM (P46009). The Busselton Healthy Ageing Study is supported by the Government of Western Australia (Office of Science, Department of Health) the City of Busselton, and private donations.

ecology↗

bioRxiv2018

Haemophilus, antibiotic therapy and the airway microbiome in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a smoking-related illness affecting 64 million people worldwide. Airway infection drives recurrent exacerbations and lung function decline. Prophylactic antibiotics may prevent exacerbations but their use is a significant cause of population antimicrobial resistance.\n\nWe characterised the sputum microbiome by 16S rRNA gene analysis using 138 samples collected during a randomised controlled trial of prophylactic antibiotics in 71 patients with stable COPD. On comparing the profile of the microbiome obtained by sequencing to the isolates grown from samples using standard culture, there were similarities overall, although with a much narrower spectrum of genera on culture with under-representation of certain genera including Veillonella and Prevotella. There was concordance in the most abundant genera within samples and the number of isolates cultured reflected the measured bacterial diversity.\n\nWe found that at baseline the microbiota of 17 (24%) patients were dominated by Haemophilus influenzae, accompanied by narrowed microbial diversity and higher levels of sputum inflammatory cytokines. Different H. influenzae strains co-existed within individuals. Opportunistic whole genome sequencing of six H. influenzae isolates obtained during the study revealed that all were non-typeable H. influenzae (NTHI), with a range of different antibiotic resistance gene profiles, but an identical complement of virulence genes.\n\nAdministration of 13 weeks prophylaxis with moxifloxacin, azithromycin or doxycycline revealed distinctive changes in microbial communities for each group. Haemophilus numbers reduced by 90% compared to placebo only after moxifloxacin, and significant reduction in sputum cytokines occurred in patients dominated by Haemophilus at baseline. Haemophilus influenzae dominance defines COPD patients with active disease who may particularly benefit from antibiotics or vaccination.

microbiology↗