Intranasal Exposure to Staphylococcal Enterotoxin B Elicits an Acute Systemic Inflammatory Response

Abstract

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.

Human Leukocyte Antigen Class II Transgenic Mouse Model Unmasks the Significant Extrahepatic Pathology in Toxic Shock Syndrome

“…Challenging HLA-II transgenic mice with SAgs thorough several different routes elicits robust SIRS and renders them highly susceptible to TSS. [40][41][42][43][44][45][46][47][48][49] One of our HLA-II transgenic lines that expresses HLA-DR3 is extremely sensitive to SEB. HLA-DR3 transgenic mice readily die of SEB-induced TSS without D-galN sensitization.…”

Staphylococcal Enterotoxins, Stayphylococcal Enterotoxin B and Bioterrorism

“…SEs have also been shown to cross polarized epithelial cells in vitro suggesting that SEs gain systemic access to the body (Hale, unpublished data). Rajagpjalan et al (2007) show acute activation of the systemic immune system and inflammatory response in mice that were vaginally or intranasally exposed to SEB (Rajagopalan et al 2007;Rajagopalan et al, 2006). Since the toxin was introduced on mucosal surfaces, the only method for systemic activation would be if the toxin crossed the epithelial cell barrier and gained access to the body.…”

Superantigens of a superbug: Major culprits ofStaphylococcus aureusdisease?

“…19 Studies in an HLA-DR transgenic mice that are more sensitive to SAgs showed that intranasal exposure to SAgs induces airway inflammation suggesting a role for SAgs in S. aureus pneumonia. 20 Spaulding et al reported significant protection against S. aureus pneumonia in rabbits using a multivalent immunization with various combinations of SAgs and cytolysins. 6 The latter study was rather surprising as vaccination with TSST-1 alone was sufficient for complete protection against USA300 LAC strain, while both a hemolysin and PVL are known to play a very critical role in protection against USA300 in the same model.…”