Neutrophilic proteolysis in the cystic fibrosis lung correlates with a pathogenic microbiome.
Quinn RA, Adem S, Mills RH, Comstock W, DeRight Goldasich L, Humphrey G, Aksenov AA, Melnik AV, da Silva R, Ackermann G, Bandeira N, Gonzalez DJ, Conrad D, O'Donoghue AJ, Knight R, Dorrestein PC
Microbiome. Feb 2019. doi: 10.1186/s40168-019-0636-3
COMMENT: In this work the microbial and molecular composition of sputum samples from Cystic Fibrosis (CF) patients are analyzed using 16S rRNA gene amplicon sequencing and mass spectrometry to analyze metabolites. The integration of these 2 types of OMICs allows to the authors concluding that proteolysis by neutrophils enzymes favoures an amino acid-rich environment in which P. aeruginosa becomes predominant.
Here we combine microbiome sequencing, metabolomics and peptidomics on adult CF sputum to analyze the relationship between microbial/chemical composition and disease severity. We use these results to propose a model of how extensive neutrophilic proteolysis in the lung generates abundant peptides and amino acids that promote the growth and persistence of pathogens, leading to more severe lung disease.
Pseudomonas aeruginosa appears to dominate the lung microbial community in Cystic Fibrosis (CF) patients:
...the lung recruits high levels of neutrophils over decades, creating a highly inflammatory environment. The microbial composition of this community has been well characterized. It has been repeatedly shown that as the disease progresses and patients age, the community diversity decreases and pathogens, particularly Pseudomonas aeruginosa, come to dominate
The integration of metabolome data and 16S taxonomic profiles data allowed grouping the CF samples in the same 2 clusters:
The microbiome profile of samples from meta-cluster 1 was enriched in anaerobic bacteria such as Streptoccoccus sp., Prevotella melaninogenica, and Veillonella dispar, whereas meta-cluster 2 was enriched in P. aeruginosa
The authors hypothesize the possible cause of the P. aeruginose persistence in the lungs of CF patients:
We hypothesize that the CF lung becomes a favored environment for persistence of P. aeruginosa in part because this bacterium promotes recruitment of neutrophils to the lung and their proteases generate peptides and amino acids that are a favored carbon source of the pathogen P. aeruginosa’s inherent resistance to neutrophilic attack, through its growth in biofilms and production of virulence factors, may explain its persistence and dominance in this amino acid rich environment.
The CF pathogen Pseudomonas aeruginosa was correlated with the abundance of amino acids and is known to primarily feed on them in the lung.In cases of severe CF lung disease, proteolysis by host enzymes creates an amino acid-rich environment that P. aeruginosa comes to dominate, which may contribute to the pathogen's persistence by providing its preferred carbon source.
The authors highlight the potential of treatments anti-neutrophil elastase (NE) and anti-cathepsin G (CG):
Our data also indicates that anti-NE and anti-CG treatments should be further investigated for their potential to reduce proteolysis in CF . These drugs may not only reduce pulmonary inflammation, as has previously been shown , but may also inhibit the growth of P. aeruginosa by reducing the availability of its primary carbon source.