Intranasal exposure to staphylococcal enterotoxin B elicits an acute systemic inflammatory response

Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Shock (Impact Factor: 3.05). 07/2006; 25(6):647-56. DOI: 10.1097/01.shk.0000209565.92445.7d
Source: PubMed


Staphylococcus aureus produces a variety of superantigen exotoxins, including staphylococcal enterotoxin B (SEB). Little is known regarding the pathogenesis of SEB entering through the intranasal route. Intranasal exposure to SEB might occur because of nasal packing following surgical procedure, biologic warfare, or even S. aureus colonization. We evaluated the local and systemic effects of intranasally delivered SEB using a series of human leukocyte antigen (HLA) class II transgenic mice as conventional mice expressing endogenous class II molecules mount a poor immune response to SEB. Gene expression profiling using microarrays showed robust up-regulation of genes involved in several proinflammatory pathways as early as 3 h post-intranasal challenge with SEB in HLA class II transgenic mice. This was accompanied by a several hundred-fold increase in serum levels of pro-inflammatory cytokines such as IL-12, IL-6, TNF-alpha, IFN-gamma, as well as MCP-1 in HLA class II transgenic mice but not in C57BL/6 mice; CD4 or CD8 T-cells independently contributed to the systemic cytokine response. Defective IL-12 or IL-4 receptor signaling significantly decreased or increased serum IFN-gamma, respectively. Intranasal exposure to SEB resulted in neutrophil influx into bronchoalveolar lavage fluid and caused expansion of both CD4 and CD8 T-cells expressing TCR V beta 8 in the spleen. This was accompanied by mononuclear cell infiltration in the liver reminiscent of the systemic inflammatory response syndrome. Thus, we have shown, for the first time, that intranasal administration of SEB can cause systemic immune activation.

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    • "MSCs have been shown to suppress production of pro-inflammatory cytokines and chemokines, including MIP-2(CXCL-2), CCL5, TNF, IL-6, and IL-1β, in animal models of lung injury and sepsis [16,18,22,27]. Therefore, we investigated whether hMSCs could modulate production of pro-inflammatory cytokines, including IL-2, IL-6, TNF and IFNγ previously implicated in the pathogenesis of experimental models of TSS [6,7,28-31]. Serum was collected from mice treated with hMSCs, or PBS as a control, at 2, 4, 6, 8, 10, 12 and 24 hours after peritoneal injection of SEB, and the serum levels of IL-2, IL-6, TNF and IFNγ were measured. "
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    ABSTRACT: Toxic shock syndrome (TSS) is caused by an overwhelming host-mediated response to bacterial superantigens produced mainly by Staphylococcus aureus and Streptococcus pyogenes. TSS is characterized by aberrant activation of T cells and excessive release of pro-inflammatory cytokines ultimately resulting in capillary leak, septic shock, multiple organ dysfunction and high mortality rates. No therapeutic or vaccine has been approved by the U.S. Food and Drug Administration for TSS, and novel therapeutic strategies to improve clinical outcome are needed. Mesenchymal stromal (stem) cells (MSCs) are stromal cells capable of self-renewal and differentiation. Moreover, MSCs have immunomodulatory properties, including profound effects on activities of T cells and macrophages in specific contexts. Based on the critical role of host-derived immune mediators in TSS, we hypothesized that MSCs could modulate the host-derived proinflammatory response triggered by Staphylococcal enterotoxin B (SEB) and improve survival in experimental TSS. Effects of MSCs on proinflammatory cytokines in peripheral blood were measured in wild-type C57BL/6 mice injected with 50 mug of SEB. Effects of MSCs on survival were monitored in fatal experimental TSS induced by consecutive doses of D-galactosamine (10 mg) and SEB (10 mug) in HLA-DR4 transgenic mice. Despite significantly decreasing serum levels of IL-2, IL-6 and TNF induced by SEB in wild-type mice, human MSCs failed to improve survival in experimental TSS in HLA-DR4 transgenic mice. Similarly, a previously described downstream mediator of human MSCs, TNF-stimulated gene 6 (TSG-6), did not significantly improve survival in experimental TSS. Furthermore, murine MSCs, whether unstimulated or pre-treated with IFNgamma, failed to improve survival in experimental TSS. Our results suggest that the immunomodulatory effects of MSCs are insufficient to rescue mice from experimental TSS, and that mediators other than IL-2, IL-6 and TNF are likely to play critical mechanistic roles in the pathogenesis of experimental TSS.
    Full-text · Article · Jan 2014 · BMC Immunology
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    • "Exposure to staphylococcal enterotoxin B (SEB) resulting from infection with Staphylococcal aureus can result in life threatening complications due to activation of up to 40% of naïve T and possibly NKT cells [1,2,3,4]. This exaggerated response leads to the production of a number of pro-inflammatory cytokines including IL-1β, IL-2, IL-6, IFN-γ, and TNF-α [5,6], which can lead to endothelial cell injury, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and vascular collapse (shock) [7]. "
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    ABSTRACT: Exposure to bacterial superantigens, such as staphylococcal enterotoxin B (SEB), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). To date, there are no known effective treatments for SEB-induced inflammation. In the current study we investigated the potential use of the hyaluronic acid synthase inhibitor 4-methylumbelliferone (4-MU) on staphylococcal enterotoxin B (SEB) induced acute lung inflammation. Culturing SEB-activated immune cells with 4-MU led to reduced proliferation, reduced cytokine production as well as an increase in apoptosis when compared to untreated cells. Treatment of mice with 4-MU led to protection from SEB-induced lung injury. Specifically, 4-MU treatment led to a reduction in SEB-induced HA levels, reduction in lung permeability, and reduced pro-inflammatory cytokine production. Taken together, these results suggest that use of 4-MU to target hyaluronic acid production may be an effective treatment for the inflammatory response following exposure to SEB.
    Full-text · Article · Oct 2013 · Toxins
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    • "AE°.HLA-DR3 transgenic mice expressing the functional HLA-DRA1*0101 and HLA-DRB1*0301 transgenes on the complete mouse MHC class II-deficient background have been described earlier and were used in this study [18]. HLA-DR3 transgenic mice are extremely sensitive to TSS without the use of any sensitizing agents and faithfully recapitulate human TSS [19]. "
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    ABSTRACT: Toxic shock syndrome (TSS) caused by the superantigen exotoxins of Staphylococcus aureus and Streptococcus pyogenes is characterized by robust T cell activation, profound elevation in systemic levels of multiple cytokines, including interferon-γ (IFN-γ), followed by multiple organ dysfunction and often death. As IFN-γ possesses pro- as well as anti-inflammatory properties, we delineated its role in the pathogenesis of TSS. Antibody-mediated in vivo neutralization of IFN-γ or targeted disruption of IFN-γ gene conferred significant protection from lethal TSS in HLA-DR3 transgenic mice. Following systemic high dose SEB challenge, whereas the HLA-DR3.IFN-γ(+/+) mice became sick and succumbed to TSS, HLA-DR3.IFN-γ(-/-) mice appeared healthy and were significantly protected from SEB-induced lethality. SEB-induced systemic cytokine storm was significantly blunted in HLA-DR3.IFN-γ(-/-) transgenic mice. Serum concentrations of several cytokines (IL-4, IL-10, IL-12p40 and IL-17) and chemokines (KC, rantes, eotaxin and MCP-1) were significantly lower in HLA-DR3.IFN-γ(-/-) transgenic mice. However, SEB-induced T cell expansion in the spleens was unaffected and expansion of SEB-reactive TCR Vβ8(+) CD4(+) and CD8(+) T cells was even more pronounced in HLA-DR3.IFN-γ(-/-) transgenic mice when compared to HLA-DR3.IFN-γ(+/+) mice. A systematic histopathological examination of several vital organs revealed that both HLA-DR3.IFN-γ(+/+) and HLA-DR3.IFN-γ(-/-) transgenic mice displayed comparable severe inflammatory changes in lungs, and liver during TSS. Remarkably, whereas the small intestines from HLA-DR3.IFN-γ(+/+) transgenic mice displayed significant pathological changes during TSS, the architecture of small intestines in HLA-DR3.IFN-γ(-/-) transgenic mice was preserved. In concordance with these histopathological changes, the gut permeability to macromolecules was dramatically increased in HLA-DR3.IFN-γ(+/+) but not HLA-DR3.IFN-γ(-/-) mice during TSS. Overall, IFN-γ seemed to play a lethal role in the immunopathogenesis of TSS by inflicting fatal small bowel pathology. Our study thus identifies the important role for IFN-γ in TSS.
    Full-text · Article · Feb 2011 · PLoS ONE
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