Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.37 (neutrophil elastase)
 4,078 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pseudomonas aeruginosa downregulates flagellin transcription when it is grown in purulent mucus from patients with cystic fibrosis (CF) and non-CF bronchiectasis. This response possibly abrogates the potent inflammatory response mediated by the interaction of flagellin with Toll-like receptor 5. The molecular mechanisms involved are thus far unknown. Known flagellar transcriptional regulators were not involved, thus Tn5 mutagenesis was used to ascertain whether novel regulators existed. Five clones with independent Tn5 insertions in flgM showed derepression of flagellin synthesis, suggesting that FlgM was involved in this phenomenon. Furthermore, examination of mucus-grown bacteria showed FlgM accumulation and overexpression of fliA in mucus-grown bacteria reversed the repression of flagellin synthesis. A related study from our laboratory had identified neutrophil elastase in mucus as the molecule responsible for fliC repression, therefore we examined whether loss of the flagellar hook (FlgE), by proteolysis was involved, because the flagellar hook is required for FlgM export. Western immunoblot of membranes from mucus-grown bacteria showed the absence of FlgE, despite the fact that the protein is made and the operon encoding FlgE is upregulated in mucus. A model is proposed wherein neutrophil elastase in mucus proteolytically cleaves the flagellar hook, thus completion of the hook basal body is never sensed, resulting in FlgM accumulation within the cell, causing repression of flagellin synthesis. We speculate that the cyclical bouts of inflammation observed in CF patients may result from flagellin synthesis and its repression, caused by presence of neutrophils at the site of infection.
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PMID:Genetic mechanisms involved in the repression of flagellar assembly by Pseudomonas aeruginosa in human mucus. 1723 27

Pseudomonas aeruginosa and Klebsiella pneumoniae are two common gram-negative pathogens that are associated with bacterial pneumonia and can often be isolated from the same patient. We used a mixed-pathogen pneumonia infection model in which mice were infected with sublethal concentrations of P. aeruginosa and K. pneumoniae, resulting in significant lethality, outgrowth of both bacteria in the lung, and systemic dissemination of K. pneumoniae. Inflammation, induced by P. aeruginosa activation of Toll-like receptor 5, results in prolonged neutrophil recruitment to the lung and increased levels of neutrophil elastase in the airway, resulting in lung damage and epithelial barrier dysfunction. Live P. aeruginosa was not required to potentiate K. pneumoniae infection, and flagellin alone was sufficient to induce lethality when delivered along with Klebsiella. Prophylaxis with an anti-Toll-like receptor 5 antibody or Sivelestat, a neutrophil elastase inhibitor, reduced neutrophil influx, inflammation, and mortality. Furthermore, pathogen-specific monoclonal antibodies targeting P. aeruginosa or K. pneumoniae prevented the outgrowth of both bacteria and reduced host inflammation and lethality. These findings suggest that coinfection with P. aeruginosa may enable the outgrowth and dissemination of K. pneumoniae, and that a pathogen- or host-specific prophylactic approach targeting P. aeruginosa may prevent or limit the severity of such infections by reducing neutrophil-induced lung damage.
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PMID:The Neutrophilic Response to Pseudomonas Damages the Airway Barrier, Promoting Infection by Klebsiella pneumoniae. 3013 Apr 23