Related Experiment Videos
Distinct roles for pneumolysin's cytotoxic and complement activities in the pathogenesis of pneumococcal pneumonia
J B Rubins1, D Charboneau, C Fasching
1Pulmonary Disease Division, Department of Medicine, Veterans Affairs Medical Center, Minneapolis, Minnesota, USA.
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.
Insights
Pneumolysin, a toxin from Streptococcus pneumoniae, has two key activities that impact pneumonia. Both hemolytic and complement activities contribute to bacterial growth and virulence during infection.
Area of Science:
- Microbiology
- Immunology
- Pathogenesis
Background:
- Streptococcus pneumoniae causes invasive pneumococcal pneumonia.
- Pneumolysin is a major cytotoxin contributing to pneumonia's early stages.
- Pneumolysin exhibits distinct hemolytic and complement-activation activities.
Purpose of the Study:
- To investigate the specific roles of pneumolysin's hemolytic and complement activities in pneumonia pathogenesis.
- To compare the in vivo effects of S. pneumoniae strains with altered pneumolysin functions.
Main Methods:
- Utilized type 2 S. pneumoniae mutant strains lacking specific pneumolysin activities.
- Administered bacterial strains via endotracheal instillation in a pulmonary infection model.
- Assessed bacterial growth, lung injury, bacteremia, and neutrophil killing in vitro.
Main Results:
- Mutant strains lacking either hemolytic or complement activity were less virulent than wild-type.
- Hemolytic activity correlated with acute lung injury and bacterial growth early in infection (3-6h).
- Complement activity correlated with bacterial growth and bacteremia later in infection (24h) and inhibited neutrophil killing.
Conclusions:
- Both hemolytic and complement activities of pneumolysin contribute distinctly to S. pneumoniae pathogenesis.
- These activities impact different stages and mechanisms of pneumococcal pneumonia.
- Understanding these functions aids in developing targeted therapeutic strategies.