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The presence of Cystic Fibrosis Related Diabetes modifies the sputum microbiome in Cystic Fibrosis disease.

ABSTRACT: The presence of Cystic Fibrosis Related Diabetes modifies the sputum microbiome in Cystic Fibrosis disease.

PROVIDER: PRJEB64339 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR12391510_1.fastq.gz	Fastqsanger.gz
	ERR12391510_2.fastq.gz	Fastqsanger.gz
	ERR12391511_1.fastq.gz	Fastqsanger.gz
	ERR12391511_2.fastq.gz	Fastqsanger.gz
	ERR12391512_1.fastq.gz	Fastqsanger.gz

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Project description:Cystic fibrosis (CF) is an inherited, multi-system disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a ubiquitous ion channel important for epithelial hydration. A direct consequence of this dysfunction is impaired mucociliary clearance, chronic airway infection and a persistent neutrophilic inflammatory response that results in progressive loss of lung function, development of respiratory failure and premature death. Partial restoration of CFTR function is now possible for most CF patients through mutation specific CFTR modulators. Ivacaftor monotherapy produces significant clinical improvement in CF patients with the G511D mutation. Dual therapy, combining ivacaftor with lumacaftor or tezacaftor, results in modest clinical improvements in patients homozygous for F508del. More recently, triple therapy with elexacaftor/tezacaftor/ivacaftor (ETI) has led to dramatic improvements in lung function and quality of life in patients homozygous and heterozygous for F508del. Sputum proteomics is a powerful research technique capable of identifying important airway disease mechanisms by interrogating the proteome, an entire set of proteins within biological samples. It has confirmed the central role of neutrophilic immune dysregulation in CF and non-CF bronchiectasis, particularly involving the release of antimicrobial proteins and neutrophil-extracellular traps (NETs), and through impaired anti-inflammatory mechanisms. These processes produce distinct molecular signatures within the sputum proteome that become increasingly abnormal with chronic airway infection and progressive lung disease severity. In CF patients, airway and systemic inflammatory cytokines potentially related to these signatures reduce with the various forms of CFTR modulation. To date, no studies of ETI therapy in CF lung disease have assessed large-scale change in protein expression using untargeted proteomics. We hypothesised that ETI therapy would shift the sputum proteome toward health, potentially normalising airway biology in people with CF. The objectives of this study were to investigate changes in the CF sputum proteome with the introduction of ETI, correlate these with changes in clinical markers of disease severity, and make comparisons with the sputum proteome in healthy controls and in repeat samples from CF patients not suitable for ETI therapy. We also explored which molecular pathways associated with CF lung disease did not change with ETI.

Project description:Hallmarks of cystic fibrosis (CF) are increased viscosity of mucus and impaired mucociliary clearance within the airways due to mutations of the cystic fibrosis conductance regulator gene. This paves the way for the colonization by microbial pathogens and the concomitant establishment of chronic infections leading to lung tissue damage, reduced lung function, and to decreased life expectancy. Although microbial infections play a key role during disease progression, only a few studies investigated the pathophysiology of the microbial community in vivo so far. Moreover, no CF study so far applied metaproteomics, a powerful approach to unravel molecular mechanisms of microbial infection, mainly reasoned due to (I) the challenging processability of inhomogeneous, viscous, slimy sputum, and (II) the high number of human proteins masking comparably low abundant microbial proteins. Consequently, we developed a reliable, reproducible and widely applicable protocol for sputum processing, microbial enrichment, and subsequent metaproteomics analyses with a focus on microbial pathogens overcoming the aforementioned challenges. Metaproteomics data were complemented and validated by 16S sequencing, metabolomic as well as microscopic analyses. In total, we processed 21 CF sputum samples and selected three for detailed metaproteome analysis. The number of bacterial proteins/protein groups increased from 199-425 to 392-868. Moreover, our data suggest that the arginine deiminase pathway and multiple proteases and peptidases identified from various bacterial genera are so far underappreciated in their contribution to the CF pathophysiology. By providing a standardized and effective protocol for sputum processing and microbial enrichment, our study represents an important basis for future studies investigating the physiology of microbial pathogens in CF in vivo – an important prerequisite for the development of novel antimicrobial therapies against mucoviscidosis.

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The presence of Cystic Fibrosis Related Diabetes modifies the sputum microbiome in Cystic Fibrosis disease.

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