INDUCTION OF TUMOR-NECROSIS-FACTOR-ALPHA BY THE GROUP-SPECIFIC AND TYPE-SPECIFIC POLYSACCHARIDES FROM TYPE-III GROUP-B STREPTOCOCCI

Previous studies suggested that circulating tumor necrosis factor alph a (TNF-alpha) may have a pathophysiologic role in experimental neonata l sepsis induced by group B streptococci (GBS). This study was underta ken to investigate the ability of the type III and group-specific poly saccharides of GBS to induce TNP-alpha production and TNF-alpha-depend ent lethality in neonatal rats. The cytokine was detected in plasma sa mples by the L929 cytotoxicity assay. Intracardiac injections of eithe r polysaccharide induced dose-dependent, transient elevations in plasm a TNF-alpha levels that returned to baseline values after 5 h. The gro up-specific antigen induced significantly higher mean peak TNF-alpha l evels than the type III antigen (125 +/- 47 versus 44 +/- 15 U/ml with 70 mg/kg of body weight). Glycogen (70 mg/kg), used as a negative con trol, did not induce TNF-alpha. The lipopolysaccharide-neutralizing ag ent polymyxin B did not decrease TNF-alpha levels induced by either po lysaccharide, ruling out contamination with endotoxin as a possible ca use of TNF-alpha induction. Fifty percent lethal doses of the type III and group-specific antigens given as intracardiac injections were 105 and 16 mg/kg, respectively. Salmonella endotoxin, used as a positive control, had a 50% lethal dose of 0.1 mg/kg. The lethal activities of GBS polysaccharides, as well as endotoxin, were completely prevented b y pretreatment of neonatal rats with the respective specific antibodie s or anti-murine TNF-alpha serum. To assess the relative importance of the type-specific substance in TNF-alpha induction by whole bacteria, two unrelated GBS transposon mutants devoid of only the type-specific capsular polysaccharide (COH1-13 and COH31-15) were employed. Each of the heat-killed unencapsulated mutants was able to produce plasma TNF -alpha level elevations or TNF-alpha-dependent lethality but was signi ficantly less efficient in these activities than the corresponding enc apsulated wild-type strain. These data suggest that the presence of ty pe-specific material on GBS is not necessary for the stimulation of TN F-alpha production. Type III capsular polysaccharide, however, can sig nificantly increase the ability of GBS to induce TNF-alpha. Further st udies will be needed to assess the importance of TNF-alpha induction b y the group- and type-specific antigens in the pathophysiology of GBS disease.