Deciphering the Ecology of Cystic Fibrosis Bacterial Communities: Towards Systems-Level Integration

Bevivino, Annamaria; Bacci, Giovanni; Dřevı́nek, Pavel; Nelson, Maria T.; Hoffman, Lucas R.; Mengoni, Alessio

doi:10.1016/j.molmed.2019.07.008

Cited by 48 publications

(47 citation statements)

References 117 publications

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“…In CF airways, infections with bacterial species such as P. aeruginosa, Burkholderia cepacia complex, Haemophilus influenza and S. aureus are well investigated [3][4][5]. However, advances in NGS have identified the presence of Prevotella spp.…”

Section: Discussionmentioning

confidence: 99%

“…The main causes of mortality and morbidity in CF are lung damage and progressive lung function decline and, attributed in part to the dehydrated mucus and bacterial infection with Gram-negative pathogens which cause a sustained inflammatory response in the CF lung [2]. The contribution of bacterial species such as Pseudomonas aeruginosa (P. aeruginosa), Burkholderia cepacia complex, Haemophilus influenza and Staphylococcus aureus (S. aureus) to inflammation in the CF lung have been extensively studied [3][4][5], however, a broader picture of the microenvironment in the CF lung has recently become apparent with advances in high fidelity next generation sequencing (NGS) [1]. This method has identified a diverse microbiome in the lungs of people with CF, including the presence of the Gramnegative anaerobic genus Prevotella spp.…”

Section: Introductionmentioning

confidence: 99%

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Toll like Receptor signalling by Prevotella histicola activates alternative NF-κB signalling in Cystic Fibrosis bronchial epithelial cells compared to P. aeruginosa

2020

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Cystic Fibrosis (CF), caused by mutations affecting the CFTR gene, is characterised by viscid secretions in multiple organ systems. CF airways contain thick mucus, creating a gradient of hypoxia, which promotes the establishment of polymicrobial infection. Such inflammation predisposes to further infection, a self-perpetuating cycle in mediated by NF-κB. Anaerobic Gram-negative Prevotella spp. are found in sputum from healthy volunteers and CF patients and in CF lungs correlate with reduced levels of inflammation. Prevotella histicola (P. histicola) can suppress murine lung inflammation, however, no studies have examined the role of P. histicola in modulating infection and inflammation in the CF airways. We investigated innate immune signalling and NF-kB activation in CF epithelial cells CFBE41o-in response to clinical stains of P. histicola and Pseudomonas aeruginosa (P. aeruginosa). Toll-Like Receptor (TLR) expressing HEK-293 cells and siRNA assays for TLRs and IKKα were used to confirm signalling pathways. We show that P. histicola infection activated the alternative NF-kB signalling pathway in CF bronchial epithelial cells inducing HIF-1α protein. TLR5 signalling was responsible for the induction of the alternative NF-kB pathway through phosphorylation of IKKα. The induction of transcription factor HIF-1α was inversely associated with the induction of the alternative NF-kB pathway and knockdown of IKKα partially restored canonical NF-kB activation in response to P. histicola. This study demonstrates that different bacterial species in the respiratory microbiome can contribute differently to inflammation, either by activating inflammatory cascades (P. aeruginosa) or by muting the inflammatory response by modulating similar or related pathways (P. histicola). Further work is required to assess the complex interactions of the lung microbiome in response to mixed bacterial infections and their effects in people with CF.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Toll like Receptor signalling by Prevotella histicola activates alternative NF-κB signalling in Cystic Fibrosis bronchial epithelial cells compared to P. aeruginosa

2020

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“…In fact, bacterial lung infections reduce life expectancy in most individuals with cystic fibrosis (CF) [ 1 ]. Many analyses of CF microbiota have been done (see for instance [ 2 , 3 ]). Most of these studies used 16S rRNA gene sequencing, yielding the identities and relative abundances of the taxa present (i.e., the microbiota).…”

Section: Introductionmentioning

confidence: 99%

“…However, 16S rRNA based analyses have strong limits in providing strain-level or functional (meaning based on functional genes) information, which are more appropriately gained by metagenomics analyses [ 4 ]. Studying the microbial genetic repertoire, e.g., antibiotic resistance and virulence-related genes, with respect to clinical status or treatment can identify mechanisms of microbial persistence and pathogenesis [ 3 , 5 , 6 ]. However, up to now, most of these studies were cross-sectional, analyzing samples collected at a single time point from individual patients.…”

Section: Introductionmentioning

confidence: 99%

Untargeted Metagenomic Investigation of the Airway Microbiome of Cystic Fibrosis Patients with Moderate-Severe Lung Disease

et al. 2020

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Although the cystic fibrosis (CF) lung microbiota has been characterized in several studies, little is still known about the temporal changes occurring at the whole microbiome level using untargeted metagenomic analysis. The aim of this study was to investigate the taxonomic and functional temporal dynamics of the lower airway microbiome in a cohort of CF patients. Multiple sputum samples were collected over 15 months from 22 patients with advanced lung disease regularly attending three Italian CF Centers, given a total of 79 samples. DNA extracted from samples was subjected to shotgun metagenomic sequencing allowing both strain-level taxonomic profiling and assessment of the functional metagenomic repertoire. High inter-patient taxonomic heterogeneity was found with short-term compositional changes across clinical status. Each patient exhibited distinct sputum microbial communities at the taxonomic level, and strain-specific colonization of both traditional and atypical CF pathogens. A large core set of genes, including antibiotic resistance genes, were shared across patients despite observed differences in clinical status, and consistently detected in the lung microbiome of all subjects independently from known antibiotic exposure. In conclusion, an overall stability in the microbiome-associated genes was found despite taxonomic fluctuations of the communities.

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“…The CF microbiome varies according to age and clinical conditions of each patient, and it is generally more diverse in the younger than in the elderly, with decreasing diversity directly correlated to the loss of pulmonary function (Cox et al, 2010;Coburn et al, 2015;Caverly and Lipuma, 2018). Studies have also pointed out fungi of the genera Candida and Aspergillus as members of CF microbiomes, mainly related to cases of pulmonary exacerbation (Bevivino et al, 2019;Soret et al, 2020). However, research and treatment have conventionally focused on bacterial pathogens with little attention to fungal species.…”

Section: Introductionmentioning

confidence: 99%

The Lung Microbiome of Three Young Brazilian Patients With Cystic Fibrosis Colonized by Fungi

Almeida

Capizzani

Tonani

et al. 2020

Front. Cell. Infect. Microbiol.

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Microbial communities infiltrate the respiratory tract of cystic fibrosis patients, where chronic colonization and infection lead to clinical decline. This report aims to provide an overview of the diversity of bacterial and fungal species from the airway secretion of three young CF patients with severe pulmonary disease. The bacterial and fungal microbiomes were investigated by culture isolation, metataxonomics, and metagenomics shotgun. Virulence factors and antibiotic resistance genes were also explored. A. fumigatus was isolated from cultures and identified in high incidence from patient sputum samples. Candida albicans, Penicillium sp., Hanseniaspora sp., Torulaspora delbrueckii , and Talaromyces amestolkiae were isolated sporadically. Metataxonomics and metagenomics detected fungal reads ( Saccharomyces cerevisiae , A. fumigatus , and Schizophyllum sp.) in one sputum sample. The main pathogenic bacteria identified were Staphylococcus aureus , Pseudomonas aeruginosa , Burkholderia cepacia complex, and Achromobacter xylosoxidans . The canonical core CF microbiome is composed of species from the genera Streptococcus, Neisseria, Rothia, Prevotella , and Haemophilus . Thus, the airways of the three young CF patients presented dominant bacterial genera and interindividual variability in microbial community composition and diversity. Additionally, a wide diversity of virulence factors and antibiotic resistance genes were identified in the CF lung microbiomes, which may be linked to the clinical condition of the CF patients. Understanding the microbial community is crucial to improve therapy because it may have the opposite effect, restructuring the pathogenic microbiota. Future studies focusing on the influence of fungi on bacterial diversity and microbial interactions in CF microbiomes will be welcome to fulfill this huge gap of fungal influence on CF physiopathology.

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Deciphering the Ecology of Cystic Fibrosis Bacterial Communities: Towards Systems-Level Integration

Cited by 48 publications

References 117 publications

Toll like Receptor signalling by Prevotella histicola activates alternative NF-κB signalling in Cystic Fibrosis bronchial epithelial cells compared to P. aeruginosa

Toll like Receptor signalling by Prevotella histicola activates alternative NF-κB signalling in Cystic Fibrosis bronchial epithelial cells compared to P. aeruginosa

Untargeted Metagenomic Investigation of the Airway Microbiome of Cystic Fibrosis Patients with Moderate-Severe Lung Disease

The Lung Microbiome of Three Young Brazilian Patients With Cystic Fibrosis Colonized by Fungi

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