Superantigen and endotoxin synergize in the induction of lethal shock

Abstract

Endotoxin (lipopolysaccharide; LPS) and superantigens (exotoxins) have been identified as potent inducers of lethal shock. While endotoxin primarily interacts with CD14 receptors on macrophages, superantigens like the staphylococcal enterotoxin B (SEB) preferentially activate T cells. Both cell types are triggered to release pro-inflammatory cytokines that in turn induce lethal shock. We analyzed whether endotoxin and superantigen interact during the induction phase of lethal shock. We report that LPS and SEB operate synergistically. Lethal doses of both inducers were reduced 100-fold when given in combination. The induced serum levels of tumor necrosis factor, interleukin-6, and interferon-gamma (IFN-gamma) were elevated and remained high for a prolonged period. Moreover, synergistic action of LPS and SEB induced lethal toxic shock even without presensitization of mice with D-galactosamine (D-GalN). Opposed to D-GalN-pretreated mice, mice injected with LPS and SEB showed less liver damage, but rather apoptosis of epithelial cells in the bowel. Cyclosporin A and treatment with anti-IFN-gamma monoclonal antibody blocked the synergistic action of LPS and SEB, indicating that T cell-derived IFN-gamma is the mediator of the observed synergism. Concomitant injection of LPS and SEB had no influence on SEB-induced T cell deletion and anergy induction. Since Gram-positive and Gram-negative bacteria can be recovered from septic blood samples, the synergistic action of endotoxin and superantigens might be relevant during lethal septicemia.

Shutdown of an acute T cell immune response to viral infection is mediated by the proapoptotic Bcl-2 homology 3-only protein Bim

“…Because pathogen clearance is followed by a decrease in cytokine levels (29), we postulate that during termination of an immune response activated T cells undergo apoptosis because of cytokine deprivation and that this death is Bim dependent but Fas independent. To test this hypothesis, we examined the T cell response to human herpes simplex virus (HSV-1) infection in Fas mutant lpr mice and Bim-deficient mice.…”

Review: D-Galactosamine lethality model: scope and limitations

“…With respect to SEB and LPS, it has been shown that when SEB and LPS are administered together, the doses that are lethal individually can be reduced 100-fold and still be lethal. 22 Such synergy was evident in both normal and D-galN-sensitized mice and could be blocked by administration of cyclosporin A and also by anti-IFN-γ mAb. In another study, it was reported that SEB was not lethal to mice even with 20 mg/mouse DgalN, but that its lethality was potentiated in these mice upon addition of LPS.…”

“…TNF is released into the circulation following challenge. 18,19,21,22,24,60 Also, protection was conferred by anti-TNF-α 60 and by anti-TNF-α/β neutralizing monoclonal antibody. 18,24 Further, sensitization to SEB lethality was evident in mice regardless of their ability to respond to LPS at the level of the macrophage, including, among other mouse strains, in C3H/HeJ mice.…”

Staphylococcal Enterotoxins, Stayphylococcal Enterotoxin B and Bioterrorism

“…The mouse remains the most common model for TSS studies, although they are not sensitive to the toxin and must be sensitized with either hepatotoxins (e.g., D-galactosamine and actinomycin D) or with endotoxin to achieve an effect (Chen et al, 1994;Nagaki et al, 1994;Blank et al, 1997;Sugiyama et al, 1964). Endotoxin is a natural component of gram-negative bacteria found in the intestines and may actually contribute to shock syndromes.…”

“…T-cell deficient mice or mice engineered to have specific cytokine deficiencies show that TNF-and T cells are both required for SE-induced lethality (Blank, et al 1997). Transgenic mice expressing human TCR/MHC class II determinants solve some problems associated with mouse lymphoid cells binding SE and SAG-sensitive mice show a biphasic release of cytokines with early TNF-a release mediating lethal shock (Faulkner et al, 2005;Rajagopalan et al, 2002).…”