Synergic activities of streptococcal pyrogenic exotoxin A and lipoteichoicacid in cytokine induction

The present study was carried out to gain insight into the mechanisms invol ved in the pathogenesis of streptococcal toxic shock syndrome (TSS) and oth er acute invasive diseases caused by Streptococcus pyogenes (GAS). Specific ally, since both whole bacteria and their soluble products are often presen t in the blood in these conditions, we sought to detect possible synergic a ctivies of somatic and extracellular products in inducing mediators release . For this purpose, whole blood cultures from healthy donors were incubated with different concentrations of streptococcal pyrogenic exotoxin A (SpeA) , which is considered a major molecular effector of TSS, heat-killed GAS an d cell-wall components such as lipoteichoic acid (LTA) and soluble peptidog lican (sPGN). Significant levels of TNF-alpha, IL-1 alpha and IFN-gamma wer e found in supernatants from cultures incubated with each of the four induc ers alone. Whole GAS and both cell-wall components were more effective (p<0 .05) than SpeA in inducing cytokine release. Whole GAS, at weight basis, wa s a more potent inducer than LTA and sPGN and LTA, at weight basis, was a m ore potent inducer than sPGN. In order to verify possible additive or syner gic effects of exotoxic and parietal compounds in inducing cytokine release , whole blood cells were incubated with mixtures of SpeA and LTA at differe nt molecular ratio. TNF-alpha, IL-1 alpha and IFN-gamma levels in supernata nts were significantly (p<0.05) higher in supernatants of cultures stimulat ed simultaneously with the two components than those of cultures stimulated with a single agent. Moreover. these levels were significantly higher than the sum of cytokine levels induced by single components. This study shows that parietal compounds can act in synergy with exotoxins in inducing the r elease of cytokines, which appear to be the major mediators of TSS.