Cross-tolerance between bacterial endotoxin and group B Streptococcus in neonatal rats

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Abstract
Although endotoxin tolerance can be induced in newborns, potential cross-tolerance to group B Streptococcus (GBS), a common Gram-positive neonatal pathogen has not been investigated. In the present study we tested the hypothesis that endotoxin or recombinant tumor necrosis factor (rTNFα) can induce tolerance to lethal injection of heat-killed GBS in rat newborn pups and vice versa. The effect of such cross-tolerance on endogenous generation of plasma TNFα was subsequently evaluated. Rat pups (18-24 h old) were pretreated intracardially (i.c.) with either phosphate buffered saline (PBS), Salmonella enteritidis endotoxin (30 μg/kg) or rTNFα (35, 70 or 140 μg/kg). The pups were pretreated for either 4, 24, 48, 96 or 240 h prior to a lethal heat-killed GBS challenge. The susceptibility of the neonates to GBS-induced mortality was dependent on the duration of the pretreatment period. At 4 h of pretreatment with endotoxin or TNF, GBS-induced mortality was augmented relative to the PBS group. However, by 24-48 h the endotoxin and TNF pretreated neonates became more resistant to GBS-induced mortality. In a converse of the above experiment, neonates were pretreated with heat killed GBS (0.7 mg/kg) or rTNFα (70 μg/kg) and sensitivity to endotoxin was determined at 4-240 h after pretreatment. The data were qualitatively similar to endotoxin pretreatment. The 4 h GBS or TNF pretreatment rendered the neonates more susceptible to endotoxin-induced mortality. However, by 24-48 h the pretreatment groups were more resistant (P < 0.05) to endotoxin than the PBS controls. Plasma TNFα levels were increased (P < 0.05) 2 h after challenge i.c. with lethal heat-killed GBS or S. enteritidis endotoxin. In the 4 h pretreatment groups that received either GBS or endotoxin and then challenged with endotoxin or GBS, respectively, the plasma TNFα response was markedly augmented (P < 0.05). By 48 h of pretreatment, however, the plasma TNFα response in these groups to the stimuli was significantly reduced (P < 0.05) compared to the PBS pretreated groups. Therefore, plasma TNFα parallels lethality induced by GBS or endotoxin pretreatment. The ability of GBS and endotoxin to induce cross tolerance suggests that common pathophysiological pathways are involved in these syndromes.

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