Proinflammatory Mediators of Toxic Shock and Their Correlation to Lethality

Bacterial exotoxins and endotoxins both stimulate proinflammatory mediators but the contribution of each individual toxin in the release of mediators causing lethal shock is incompletely understood. This study examines the cytokine response and lethality of mice exposed to varying doses of staphylococcal enterotoxin B (SEB) or lipopolysaccharide (LPS) and their combinations. In vivo, SEB alone induced moderate levels of IL-2 and MCP-1 and all mice survived even with a high dose of SEB (100 μg/mouse). LPS (80 μg/mouse) caused 48% lethality and induced high levels of IL-6 and MCP-1. SEB induced low levels of TNFα, IL-1, IFNγ, MIP-2, and LPS synergized with SEB in the expression of these cytokines and that of IL-6 and MCP-1. Importantly, the synergistic action of SEB and LPS resulted in lethal shock and hypothermia. ANOVA of cytokine levels by survival status of SEB-plus-LPS groups revealed significantly higher levels of TNFα, IL-6, MIP-2, and MCP-1 in nonsurvivors measured at 8 hours. Significantly higher levels of IFNγ and IL-2 were observed at 21 hours in nonsurvivors of toxic shock compared to those in survivors. Overall, synergistic action of SEB and LPS resulted in higher and prolonged levels of these key cytokines leading to toxic shock

Intranasal Rapamycin Rescues Mice from Staphylococcal Enterotoxin B-Induced Shock

Staphylococcal enterotoxin B (SEB) and related exotoxins produced by Staphylococcus aureus are potent activators of the immune system and cause toxic shock in humans. Currently there is no effective treatment except for the use of intravenous immunoglobulins administered shortly after SEB exposure. Intranasal SEB induces long-lasting lung injury which requires prolonged drug treatment. We investigated the effects of rapamycin, an immunosuppressive drug used to prevent graft rejection, by intranasal administration in a lethal mouse model of SEB-induced shock. The results show that intranasal rapamycin alone delivered as late as 17 h after SEB protected 100% of mice from lethal shock. Additionally, rapamycin diminished the weight loss and temperature fluctuations elicited by SEB. Intranasal rapamycin attenuated lung MCP-1, IL-2, IL-6, and IFNγ by 70%, 30%, 64%, and 68% respectively. Furthermore, short courses (three doses) of rapamycin were sufficient to block SEB-induced shock. Intranasal rapamycin represents a novel use of an immunosuppressant targeting directly to site of toxin exposure, reducing dosages needed and allowing a wider therapeutic window

Therapeutic Down-Modulators of Staphylococcal Superantigen-Induced Inflammation and Toxic Shock

Staphylococcal enterotoxin B (SEB) and related superantigenic toxins are potent stimulators of the immune system and cause a variety of diseases in humans, ranging from food poisoning to toxic shock. These toxins bind directly to major histocompatibility complex (MHC) class II molecules on antigen-presenting cells and specific Vβ regions of T-cell receptors (TCR), resulting in hyperactivation of both monocytes/macrophages and T lymphocytes. Activated host cells produce massive amounts of proinflammatory cytokines and chemokines, activating inflammation and coagulation, causing clinical symptoms that include fever, hypotension, and shock. This review summarizes the in vitro and in vivo effects of staphylococcal superantigens, the role of pivotal mediators induced by these toxins in the pathogenic mechanisms of tissue injury, and the therapeutic agents to mitigate the toxic effects of superantigens

The association between a body shape index and cardiovascular risk in overweight and obese children and adolescents

A Body Shape Index (ABSI) and normalized hip circumference (Hip Index, HI) have been recently shown to be strong risk factors for mortality and for cardiovascular disease in adults. We conducted an observational cross-sectional study to evaluate the relationship between ABSI, HI and cardiometabolic risk factors and obesity-related comorbidities in overweight and obese children and adolescents aged 2±18 years. We performed multivariate linear and logistic regression analyses with BMI, ABSI, and HI age and sex normalized z scores as predictors to examine the association with cardiometabolic risk markers (systolic and diastolic blood pressure, fasting glucose and insulin, total cholesterol and its components, transaminases, fat mass%detected by bioelectrical impedance analysis) and obesity- related conditions (including hepatic steatosis and metabolic syndrome). We recruited 217 patients (114 males), mean age 11.3 years. Multivariate linear regression showed a significant association of ABSI z score with 10 out of 15 risk markers expressed as continuous variables, while BMI z score showed a significant correlation with 9 and HI only with 1. In multivariate logistic regression to predict occurrence of obesity-related conditions and above-threshold values of risk factors, BMI z score was significantly correlated to 7 out of 12, ABSI to 5, and HI to 1. Overall, ABSI is an independent anthropometric index that was significantly associated with cardiometabolic risk markers in a pediatric population affected by overweight and obesity

Stimulant-Dependent Modulation of Cytokines and Chemokines by Airway Epithelial Cells: Cross Talk between Pulmonary Epithelial and Peripheral Blood Mononuclear Cells

Staphylococcal exotoxins (SE) and lipopolysaccharide (LPS) stimulate cells of the immune system to produce proinflammatory cytokines and chemokines which mediate septic shock and acute lung inflammation. A coculture of human peripheral blood mononuclear cells (PBMC) and pulmonary A549 epithelial cells was used to investigate inflammatory responses triggered by staphylococcal enterotoxin B (SEB), toxic shock syndrome toxin 1, and LPS. The levels of interleukin 1β (IL-1β), IL-6, gamma interferon-inducible protein 10, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1α, and RANTES were enhanced by 3.8-, 4.2-, 3.1-, 8.9-, 2-, and 2.9-fold, respectively, in cocultures of SEB-stimulated cells compared to in SEB-stimulated PBMC. In LPS-stimulated cocultures, only MCP-1 and RANTES levels were increased. These data suggest that the modulation of specific cytokines and chemokines is dependent on the stimulus and that there is bidirectional interaction between PBMC and lung epithelial cells to influence the immune response to these different stimuli

Update on Staphylococcal Superantigen-Induced Signaling Pathways and Therapeutic Interventions

Staphylococcal enterotoxin B (SEB) and related bacterial toxins cause diseases in humans and laboratory animals ranging from food poisoning, acute lung injury to toxic shock. These superantigens bind directly to the major histocompatibility complex class II molecules on antigen-presenting cells and specific Vβ regions of T-cell receptors (TCR), resulting in rapid hyper-activation of the host immune system. In addition to TCR and co-stimulatory signals, proinflammatory mediators activate signaling pathways culminating in cell-stress response, activation of NFκB and mammalian target of rapamycin (mTOR). This article presents a concise review of superantigen-activated signaling pathways and focuses on the therapeutic challenges against bacterial superantigens

Inflammasomes, Autophagy, and Cell Death: The Trinity of Innate Host Defense against Intracellular Bacteria

Inflammasome activation is an innate host defense mechanism initiated upon sensing pathogens or danger in the cytosol. Both autophagy and cell death are cell autonomous processes important in development, as well as in host defense against intracellular bacteria. Inflammasome, autophagy, and cell death pathways can be activated by pathogens, pathogen-associated molecular patterns (PAMPs), cell stress, and host-derived damage-associated molecular patterns (DAMPs). Phagocytosis and toll-like receptor (TLR) signaling induce reactive oxygen species (ROS), type I IFN, NFκB activation of proinflammatory cytokines, and the mitogen-activated protein kinase cascade. ROS and IFNγ are also prominent inducers of autophagy. Pathogens, PAMPs, and DAMPs activate TLRs and intracellular inflammasomes, inducing apoptotic and inflammatory caspases in a context-dependent manner to promote various forms of cell death to eliminate pathogens. Common downstream signaling molecules of inflammasomes, autophagy, and cell death pathways interact to initiate appropriate measures against pathogens and determine host survival as well as pathological consequences of infection. The integration of inflammasome activation, autophagy, and cell death is central to pathogen clearance. Various pathogens produce virulence factors to control inflammasomes, subvert autophagy, and modulate host cell death in order to evade host defense. This review highlights the interaction of inflammasomes, autophagy, and host cell death pathways in counteracting Burkholderia pseudomallei, the causative agent of melioidosis. Contrasting evasion strategies used by B. pseudomallei, Mycobacterium tuberculosis, and Legionella pneumophila to avoid and dampen these innate immune responses will be discussed

Sulfasalazine Attenuates Staphylococcal Enterotoxin B-Induced Immune Responses

Staphylococcal enterotoxin B (SEB) and related exotoxins are important virulence factors produced by Staphylococcus aureus as they cause human diseases such as food poisoning and toxic shock. These toxins bind directly to cells of the immune system resulting in hyperactivation of both T lymphocytes and monocytes/macrophages. The excessive release of proinflammatory cytokines from these cells mediates the toxic effects of SEB. This study examined the inhibitory activities of an anti-inflammatory drug, sulfasalazine, on SEB-stimulated human peripheral blood mononuclear cells (PBMC). Sulfasalazine dose-dependently inhibited tumor necrosis factor α, interleukin 1 (IL-1) β, IL-2, IL-6, interferon γ (IFNγ), and various chemotactic cytokines from SEB-stimulated human PBMC. Sulfasalazine also potently blocked SEB-induced T cell proliferation and NFκB activation. These results suggest that sulfasalazine might be useful in mitigating the toxic effects of SEB by blocking SEB-induced host inflammatory cascade and signaling pathways

PI3K/Akt/mTOR, a Pathway Less Recognized for Staphylococcal Superantigen-Induced Toxicity

Immunostimulating staphylococcal enterotoxin B (SEB) and related superantigenic toxins cause diseases in humans and laboratory animals by activating cells of the immune system. These toxins bind directly to the major histocompatibility complex (MHC) class II molecules on antigen-presenting cells and specific Vβ regions of T-cell receptors (TCR), resulting in hyperactivation of both T lymphocytes and monocytes/macrophages. Activated host cells produce excessive amounts of proinflammatory cytokines and chemokines, especially tumor necrosis factor α, interleukin 1 (IL-1), IL-2, interferon γ (IFNγ), and macrophage chemoattractant protein 1 causing clinical symptoms of fever, hypotension, and shock. The well-explored signal transduction pathways for SEB-induced toxicity downstream from TCR/MHC ligation and interaction of cell surface co-stimulatory molecules include the mitogen-activated protein kinase cascades and cytokine receptor signaling, culminating in NFκB activation. Independently, IL-2, IFNγ, and chemokines from activated T cells signal via the phosphoinositide 3-kinase (PI3K), the serine/threonine kinases, Akt and mammalian target of rapamycin (mTOR) pathways. This article reviews the signaling molecules induced by superantigens in the activation of PI3K/Akt/mTOR pathways leading to staphylococcal superantigen-induced toxicity and updates potential therapeutics against superantigens