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Inhibition of in vitro human lymphocyte response by the pneumococcal toxin pneumolysin
Abstract:
The effects of pneumolysin, a sulfhydryl-activated cytolytic toxin produced by Streptococcus pneumoniae, on the in vitro human lymphocyte response was examined. The toxin, at concentrations of one to five hemolytic units per ml, caused marked inhibition of the response of lymphocytes to concanavalin A, phytohemagglutinin, pokeweed mitogen, and protein A. The response was assessed by measuring both [3H]thymidine incorporation and the ability of lymphocytes to produce immunoglobulins and lymphokine activity. The effects of pneumolysin were irreversible, could be prevented by pretreatment of the toxin with cholesterol, and were not related to a direct cytotoxic effect on the lymphocytes. Pneumolysin appeared to act at the initiation phase of the immune response and had no effect on lymphocytes committed to DNA synthesis or to the synthesis and secretion of immunoglobulins. Furthermore, pneumolysin-mediated inhibition of the lymphocyte response was not due to the inhibition of binding of mitogens to leukocytes and is likely to be related to effects on membrane-mediated signals essential for lymphocyte triggering. This may be one means by which pneumolysin plays a role in the pathogenesis of pneumococcal infections.
Insights
Pneumolysin, a toxin from Streptococcus pneumoniae, significantly inhibits human lymphocyte responses to mitogens. This immune suppression, crucial for pneumococcal infection pathogenesis, occurs early in the immune response.
Area of Science:
- Immunology
- Microbiology
- Toxicology
Background:
- Streptococcus pneumoniae produces pneumolysin, a cytolytic toxin.
- Pneumolysin's role in pneumococcal infection pathogenesis is significant.
- Understanding pneumolysin's impact on the human immune system is crucial.
Purpose of the Study:
- To examine the effects of pneumolysin on in vitro human lymphocyte response.
- To determine the mechanism by which pneumolysin affects lymphocytes.
- To elucidate pneumolysin's contribution to pneumococcal infection pathogenesis.
Main Methods:
- In vitro assessment of human lymphocyte response to mitogens (concanavalin A, phytohemagglutinin, pokeweed mitogen, protein A).
- Measurement of [3H]thymidine incorporation and immunoglobulin/lymphokine production.
- Evaluation of pneumolysin's effects, including reversibility, prevention by cholesterol, and cytotoxicity.
Main Results:
- Pneumolysin markedly inhibited lymphocyte responses to multiple mitogens.
- Inhibitory effects were irreversible and preventable by cholesterol pretreatment.
- Pneumolysin acted at the immune response initiation phase, not affecting DNA synthesis or immunoglobulin production.
- Inhibition was not due to blocked mitogen binding but likely affected membrane-mediated signaling.
Conclusions:
- Pneumolysin inhibits human lymphocyte activation by interfering with early signaling events.
- The toxin's effects are not cytotoxic but target crucial membrane-mediated signals.
- Pneumolysin's immunomodulatory activity is a key factor in the pathogenesis of Streptococcus pneumoniae infections.