Platelet-Activating Factor Receptor Contributes to Host Defense against Pseudomonas aeruginosa Pneumonia but Is Not Essential for the Accompanying Inflammatory and Procoagulant Response

Abstract

Pseudomonas aeruginosa is a major cause of nosocomial pneumonia, which is associated with high morbidity and mortality. Because of its ubiquitous nature and its ability to develop resistance to antibiotics, it is a problematic pathogen from a treatment perspective. Platelet-activating factor receptor (PAFR) is involved in phagocytosis of several pathogens. To determine the role of PAFR in the innate immune response to P. aeruginosa pneumonia, pafr gene-deficient (PAFR−/−) mice and normal wild-type (Wt) mice were intranasally inoculated with P. aeruginosa. PAFR deficiency impaired host defense as reflected by increased bacterial outgrowth and dissemination in mice with a targeted deletion of the PAFR gene. PAFR−/− neutrophils showed a diminished phagocytosing capacity of P. aeruginosa in vitro. Relative to Wt mice, PAFR−/− mice demonstrated increased lung inflammation and injury as reflected by histopathology, relative lung weights and total protein concentrations in bronchoalveolar lavage fluid, which was accompanied by higher levels of proinflammatory cytokines in lung homogenates and plasma. In addition, PAFR deficiency was associated with exaggerated local and systemic activation of coagulation as determined by fibrin staining of lung tissue and pulmonary and plasma concentrations of thrombin-antithrombin complexes and D-dimer. These data suggest that PAFR is an essential component of an effective host response to P. aeruginosa pneumonia, at least partly via its contribution to the phagocytic properties of professional granulocytes. Additionally, our results indicate that PAFR signaling is not essential for the induction of a local and systemic inflammatory and procoagulant response to Pseudomonas pneumonia.

Lysine Trimethylation of EF-Tu Mimics Platelet-Activating Factor To Initiate Pseudomonas aeruginosa Pneumonia

“…5B). However, as previously described (13), 24 h postinfection, PAFR −/− mice were more susceptible to the infection by PAO1 than were the wild-type mice, likely due to defects in phagocytosis. Thus, PAFR contributes to resistance to P. aeruginosa respiratory infection by recognition of trimethylated EF-Tu, a posttranslational modification which is drastically reduced at 37°C.…”

CCAAT/enhancer-binding protein δ facilitates bacterial dissemination during pneumococcal pneumonia in a platelet-activating factor receptor-dependent manner

“…Indeed, PAFR-dependent transcytosis is facilitated by PC (13), and thus PC-negative E. coli will not disseminate in a PAFR-dependent manner (20). However, the fact that host defenses against PC-positive Pseudomonas aeruginosa are aggravated in PAFR −/− mice (21) suggests that an alternative mechanism may be responsible, at least in part.…”

Group A Streptococcus Secreted Esterase Hydrolyzes Platelet-Activating Factor to Impede Neutrophil Recruitment and Facilitate Innate Immune Evasion

“…This is the first demonstration for the importance of the PAF receptor in neutrophil recruitment in response to a bacterial infection. The PAF receptor is not critical for neutrophil infiltration in pulmonary Klebsiella pneumonia , Pseudomonas aeruginosa , Streptococcus pneumoniae infections and polymicrobial sepsis caused by cecum ligation and puncture [50], [51], [52], [53]. This difference suggests that PAF may play a critical role in neutrophil recruitment in skin infection but not in pulmonary infections.…”