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Amino acid changes affecting the activity of pneumolysin alter the behaviour of pneumococci in pneumonia
J E Alexander1, A M Berry, J C Paton
1Department of Microbiology and Immunology, University of Leicester, Leicester, LE1 9HN, U.K.
Abstract:
Pneumolysin is a multi-functional toxin produced by Streptococcus pneumoniae. The toxin has distinct cytotoxic activity and complement-activating activity mediated by different parts of the toxin molecule. Mice challenged intranasally with a type 2 pneumococcal strain contract bronchopneumonia and bacteremia [1]. Mice were infected intranasally with isogenic mutants of this strain in which the chromosomal pneumolysin gene carried point mutations affecting either or both properties of pneumolysin. Reduction in either cytotoxic activity or complement activation by pneumolysin decreased the virulence of the mutant pneumococci. However, it was the ability to activate complement that most affected the behaviour of pneumococci in the lungs and associated bacteremia in the first 24 h following infection.
Insights
Pneumolysin, a Streptococcus pneumoniae toxin, has cytotoxic and complement-activating activities. Complement activation by pneumolysin significantly impacts lung behavior and bacteremia in mice during early infection.
Area of Science:
- Microbiology
- Immunology
- Toxicology
Background:
- Streptococcus pneumoniae causes pneumonia and bacteremia.
- Pneumolysin is a key toxin produced by S. pneumoniae.
- Pneumolysin exhibits both cytotoxic and complement-activating functions.
Purpose of the Study:
- To investigate the distinct roles of pneumolysin's cytotoxic and complement-activating activities in S. pneumoniae virulence.
- To determine which pneumolysin function is more critical for early infection outcomes in a mouse model.
Main Methods:
- Generation of isogenic mutants of S. pneumoniae with altered pneumolysin activities.
- Intranasal infection of mice with wild-type and mutant strains.
- Assessment of bronchopneumonia, bacteremia, and bacterial behavior in the lungs.
Main Results:
- Reducing either cytotoxic or complement-activating activity decreased pneumococcal virulence.
- Complement activation by pneumolysin was found to be the primary driver of early lung pathology and bacteremia.
- The effect of complement activation on virulence was most pronounced within the first 24 hours post-infection.
Conclusions:
- Pneumolysin's complement-activating function is critical for the early stages of S. pneumoniae infection.
- Targeting pneumolysin's complement activation may be a viable strategy to combat pneumococcal disease.