Dexamethasone Attenuates Staphylococcal Enterotoxin B-Induced Hypothermic Response and Protects Mice from Superantigen-Induced Toxic Shock

Abstract

The superantigenic staphylococcal enterotoxins are important virulence factors and contribute to various diseases, including food poisoning and toxic shock. Dexamethasone, an anti-inflammatory agent, attenuated staphylococcal enterotoxin B (SEB)-induced hypothermia and serum proinflammatory cytokines and improved survival from 0% to 86% in a lethal mouse model of SEB-mediated shock.Staphylococcal enterotoxin B (SEB) and related superantigenic toxins are potent activators of the immune system and cause a myriad of maladies, ranging from food poisoning to potentially life-threatening toxic shock (13,17,21,24). These toxins bind directly to the major histocompatibility complex (MHC) class II molecules on antigen-presenting cells (17,20,22) and stimulate T cells via specific V␤ regions of the T-cell receptors (TCR) (5, 17), resulting in activation of both monocytes/macrophages and T lymphocytes. The specific interaction of these microbial toxins with multiple cell types in the host leads to excessive production of proinflammatory cytokines, chemokines, and tissue factor, causing clinical symptoms that include fever, hypotension, and shock (13,18,24). Two key inflammatory cytokines, interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-␣), are direct mediators of fever, hypotension, and shock (15). Additionally, gamma interferon (IFN-␥) from superantigen-activated T cells acts synergistically with IL-1 and TNF-␣ to enhance immune reactions and tissue injury.At present, there is no available therapeutic for treating staphylococcal exotoxin-induced shock except for the use of intravenous immunoglobulins (6). Most therapeutic strategies for experimental animal models of SEB-induced shock have targeted proinflammatory cytokines, as there is a strong correlation between toxicity and increased serum levels of these inflammatory mediators (4,11,16,19,26). These therapeutics include cytokine inhibitors and signal transduction inhibitors that target SEB-induced cellular activation pathways (10, 16). Experimental approaches aimed at disrupting toxin interactions with receptors and costimulatory molecules on macrophages and lymphocytes have also been used by different laboratories (2, 9, 10, 28). Thus, bispecific chimeric inhibitors, composed of the DR␣1 domain of MHC class II and the V␤ domain of the TCR connected by a flexible linker, were designed to bind SEB competitively and prevent binding to MHC class II of antigen-presenting cells and the TCR on T cells (9).Conserved peptides corresponding to residues 150 to 161 of SEB can act as an antagonist and prevent SEA-, SEB-, or toxic shock syndrome toxin 1-induced lethal shock in mice when given intravenously 30 min after an intraperitoneal (i.p.) toxin dose (2). This segment of SEB is not associated with the classically defined MHC class II or TCR binding domains, but it may block costimulatory signals necessary for T-cell activation. However, a subsequent study of these peptides indicates that they are ineffective inhibitors of SEB-induced effects both in vitro and in viv...

Interference of the T Cell and Antigen-Presenting Cell Costimulatory Pathway Using CTLA4-Ig (Abatacept) Prevents Staphylococcal Enterotoxin B Pathology

“…Prophylactic treatment of mice with abatacept reduced mortality after exposure to the superantigen toxic shock syndrome toxin (TSST) by 75% (33). Treatment of SEB exposure by dexamethasone and rapamycin also reduced mortality (10,34). However, rapamycin and dexamethasone treatment was given 5 h after exposure and required additional administration at 24 h timepoints for 4 d after intoxication.…”

“…Ideally, an effective treatment for superantigen exposure should only require a single dose to minimize the logistic constraints in a mass casualty situation and facilitate management of milder forms of the disease, such as food poisoning (9,10). Treatment of superantigen exposure will need to occur within a manageable postexposure window, allowing the time for detection and diagnosis required for effective treatment.…”

Rapamycin Protects Mice from Staphylococcal Enterotoxin B-Induced Toxic Shock and Blocks Cytokine ReleaseInVitroandIn Vivo

“…Staphylococcal enterotoxin B (SEB) and the distantly related toxic shock syndrome toxin 1 are also called superantigens because they induce massive proliferation of T cells (29). In vitro and in vivo studies show that these superantigens induce high levels of various proinflammatory cytokines, and these potent mediators cause lethal shock in animal models (1,6,22,27,37,39,45,51,55). SEB also causes food poisoning (4, 21, 52) and is a potential bioterrorism threat agent, as humans are extremely sensitive to this superantigen, especially by inhalation (28).…”

“…There is currently no effective therapeutic treatment for SEB-induced shock except for the use of intravenous immunoglobulins (11). Various in vitro experiments identified inhibitors to counteract the biological effects of SEB, only some of which were successful in ameliorating SEB-induced shock in experimental models (1,(25)(26)(27)51).Rapamycin is a relatively new FDA-approved drug used to prevent graft rejection in renal transplantation, as it shows less nephrotoxicity than do calcineurin inhibitors (14,40,43,48). Recent studies reveal other uses in animal models of cancer (23, 34), diabetic nephropathy (36), bleomycin-induced pulmonary fibrosis (31), liver fibrosis (5), and tuberous sclerosis (32).…”

“…The therapeutic efficacy of rapamycin in SEB-induced toxic shock was investigated by using a lethal murine model with intranasal delivery of SEB (22). This "double-hit" murine model relies on two low doses of SEB without the use of sensitizing agents such as lipopolysaccharide (LPS) or galactosamine to induce lethal shock (6,27,33,37,45). In this "SEB-only" toxic shock model, SEB was administered intranasally (i.n.)…”