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 [3HJthymidine 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 Iymphocytes. 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 membranemediated signals essential for lymphocyte triggering. This may be one means by which pneumolysin plays a role in the pathogenesis of pneumococcal infections.

Activation of Cell‐Mediated Immunity Following Immunization with Pneumococcal Conjugate or Polysaccharide Vaccine*

“…According to our results, the vaccination with plain PS is followed by a situation in which the lymphocyte proliferative responses to the protein antigens tested declined by day 14. It is difficult to know whether this is related to the pathogenesis of pneumococcal infections, as the pneumococcal protein antigen can inhibit mitogenic proliferative responses and antibody synthesis [27]. On the other hand, we have observed a comparable immunosuppressive influence of ongoing bacterial [28] infections on in vitro proliferative responses to that of nonrelated protein antigens and have regarded it as being as a result of active ongoing immunological reactions against the microbe in question.…”

Reduced virulence of a defined pneumolysin-negative mutant of Streptococcus pneumoniae

“…Nevertheless, there is an increasing body of evidence that pneumolysin, a thiol-activated toxin produced by virtually all clinical isolates of S. pneumoniae, is directly involved in pathogenesis. In vitro studies showed that very low doses of purified pneumolysin inhibit the bactericidal properties of human polymorphonuclear leukocytes and macrophages (16,18) as well as the proliferative response of human lymphocytes to mitogens (7). Higher toxin doses also cause activation of the classical complement pathway and depletion of serum opsonic activity (20).…”

Contribution of autolysin to virulence of Streptococcus pneumoniae

“…For this reason, we have been studying the role of pneumococcal protein toxins, in particular pneumolysin and neuraminidase, in pneumococcal pathogenesis. We have shown that pneumolysin has a variety of detrimental effects in vitro on components of the human immune system (7,23,25,27). Immunization of mice with purified pneumolysin also confers partial protection against challenge with virulent pneumococci (26).…”