Distinct roles for pneumolysin's cytotoxic and complement activities in the pathogenesis of pneumococcal pneumonia.

Abstract

Pneumolysin, the major Streptococcus pneumoniae cytotoxin, contributes to the early pathogenesis of invasive pneumococcal pneumonia by facilitating intrapulmonary bacterial growth and invasion into the blood. Pneumolysin is a multifunctional toxin, with distinct cytolytic ("hemolytic") and complement-activation ("complement") activities that have been mapped to several regions of the molecule. To characterize the specific contributions of pneumolysin's hemolytic and complement properties to the pathogenesis of pneumococcal pneumonia, we compared the in vivo effects of type 2 S. pneumoniae mutant strains, which produce pneumolysins deficient in these activities. The absence of either pneumolysin's hemolytic or complement activities rendered mutant strains less virulent than the wild-type strain during pulmonary infection. Pneumolysin's hemolytic activity correlated with acute lung injury and bacterial growth at 3 and 6 h after endotracheal instillation. In contrast, pneumolysin's complement activity correlated with bacterial growth and bacteremia at 24 h after pulmonary infection. Pneumolysin's complement activity was not associated with the degree of alveolar-capillary injury or recruitment of leukocytes during initial pulmonary infection. However, pneumolysin's complement activity inhibited killing of mutant bacteria in an in vitro complement-dependent neutrophil killing assay. Thus, both pneumolysin's hemolytic and complement activities made specific contributions to the early pathogenesis of pneumococcal pneumonia at different stages of infection and by different mechanisms.

Neutrophil-Toxin Interactions Promote Antigen Delivery and Mucosal Clearance ofStreptococcus pneumoniae

“…The ability of pneumolysin to aggregate into pores has also been suggested to promote virulence of the pathogen (41,42). Recently, however, a study by Kirkham et al called this idea into question, as more than half of the type 1 strains isolated from patients with invasive pneumococcal disease were shown to contain mutations in the pneumolysin gene, rendering the bacteria unable to form pores (43).…”

Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema

“…Intriguingly, edema formation can occur days after the initiation of antibiotic therapy, when tissues are sterile and the pneumonia is clearing and correlates with the presence of the bacterial virulence factor pneumolysin (PLY) (4,5). PLY is a 53-kDa cytoplasmic thiol-activated toxin released during pneumococcal lysis and is implicated in the pathogenesis of pneumococcal disease.…”

“…PLY is a 53-kDa cytoplasmic thiol-activated toxin released during pneumococcal lysis and is implicated in the pathogenesis of pneumococcal disease. This protein has cytolytic and complement-activating properties (4). Lung injury induced by PLY was suggested to result from direct pneumotoxic effects on the alveolar-capillary barrier rather than from resident or recruited phagocytic cells (6).…”

Important Role for CC Chemokine Ligand 2-Dependent Lung Mononuclear Phagocyte Recruitment to Inhibit Sepsis in Mice Infected with Streptococcus pneumoniae

“…The pathogenicity of S. pneumoniae is largely defined by its arsenal of virulence factors, among which the pore-forming cytolysin pneumolysin plays a significant role in pneumococcal cytotoxicity against resident alveolar macrophages and epithelial cells (2)(3)(4). S. pneumoniae-triggered replacement of resident alveolar macrophages by newly recruited exudate macrophages was recently shown by our group to follow remarkable kinetics, with an exchange of resident against exudate macrophages within 3-4 days of infection (5)(6)(7).…”