The Neutrophilic Response to Pseudomonas Damages the Airway Barrier, Promoting Infection by Klebsiella pneumoniae.
Omari Jones-NelsonJamese J HilliardAntonio DiGiandomenicoPaul WarrenerAlex AlfaroLily ChengC Kendall StoverTaylor S CohenBret R SellmanPublished in: American journal of respiratory cell and molecular biology (2019)
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.
Keyphrases
- toll like receptor
- klebsiella pneumoniae
- multidrug resistant
- gram negative
- oxidative stress
- nuclear factor
- acinetobacter baumannii
- inflammatory response
- escherichia coli
- drug resistant
- pseudomonas aeruginosa
- immune response
- diabetic rats
- respiratory tract
- candida albicans
- cystic fibrosis
- cancer therapy
- drug induced
- cardiovascular disease
- type diabetes
- adipose tissue
- metabolic syndrome
- high glucose
- cardiovascular events
- mechanical ventilation
- high fat diet induced
- risk factors