Murine Lethal Toxic Shock Caused by Intranasal Administration of Staphylococcal Enterotoxin B

Abstract

Currently available murine staphylococcal enterotoxin B (SEB) shock models require pretreatment with various agents to increase mouse sensitivity to SEB. This study was performed to show that C3H/HeJ mice are highly susceptible to intranasal SEB inoculation, which caused toxic shock without using pretreatment agents. For this purpose, mice were injected intranasally with different doses of SEB and observed for up to 1 month. The median lethal dose of SEB was determined using the probit procedure. Tissue samples were taken at different time points for histopathological examination. The LD 50 was found at 1.6 µg/g (95% fiducial limit (f.l.) 0.7 to 2.2), the LD 80 at 2.7 µg/g (95% f.l. 1.9 to 4.0) and the LD 90 at 3.6 µg/g (95% f.l. 2.7 to 6.4). Histopathologic examination revealed pulmonary edema and bronchopneumonia. Mucosal-associated lymphoid tissue first became activated, followed by increasing lymphocyte apoptosis and depletion. In the liver there were intralobular and portal inflammatory foci with increasing lymphocyte apoptosis and degenerative necrosis. The splenic white pulp was characterized by early activation and subsequent depletion of lymphoid follicle germinal centers. The thymus initially was activated, followed by increasing apoptosis and migration of lymphoid cells from the cortex to the medulla. The pathological features detected in the mice were similar to those of rhesus monkeys treated with SEB aerosol challenge.

Δ9Tetrahydrocannabinol attenuates Staphylococcal enterotoxin B‐induced inflammatory lung injury and prevents mortality in mice by modulation of miR‐17‐92 cluster and induction of T‐regulatory cells

“…Consequently, SEB exposure leads to the massive release of inflammatory cytokines, proliferation of T‐cells, tissue damage and SEB‐mediated shock (Miethke et al ., ; DeVries et al ., ; Kissner et al ., ). Most models developed to study the effects of SEB exposure in mice, have employed the use of transgenic mice or external agents such as LPS or D‐galactosamine to potentiate SEB‐mediated inflammatory response (DaSilva et al ., ; Savransky et al ., ). In the dual administration of SEB as used in this study, microgram quantities of SEB were sufficient to cause inflammatory symptoms and toxicity reminiscent of SEB exposure in humans (Huzella et al ., ).…”

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

“…SEB is more toxic via inhalation, compared with ingestion, and severe lung damage after exposure to SEB aerosols has been demonstrated (23). Numerous animal models of SEB intoxication have been developed that use survival as a primary outcome for the efficacy of medical countermeasures (24,25). However, weaponized SEB has potential incapacitating properties for exposed military personnel because of the ED 50 (the median effective dose of incapacitation) being ∼50 times lower than the LD 50 (26,27).…”

Effective Treatment of Staphylococcal Enterotoxin B Aerosol Intoxication in Rhesus Macaques by Using Two Parenterally Administered High-Affinity Monoclonal Antibodies

“…Inhaled SEB initiates a nearly instantaneous response in the lungs after inhalation, marked by neutrophilic influx, massive cytokine release, and marked pathological changes (10–14). Major osmotic shifts in the lung tissue from SEB inhalation result in a primarily localized inflammatory response which leads to progressive vascular leak, microcapillary hemorrhage, and alveolar flooding (10, 15, 16). The use of animal models of SEB intoxication to evaluate potential treatments is complicated by decreasing sensitivity based upon phylogenetic evolution; murine species are generally unresponsive to SEB unless genetically manipulated (17) or the reaction is potentiated by coadministration of an agent such as lipopolysaccharide (LPS) (15, 18).…”