Aerosolized Staphylococcal Enterotoxin B-Induced Pulmonary Lesions in Rhesus Monkeys (Macaca mulatta)

Abstract

The pathology of aerosolized staphylococcal enterotoxin B (SEB) was studied in the nonhuman primate. Six juvenile rhesus monkeys that received multiple lethal inhaled doses of SEB developed diarrhea and vomiting within 24 hr followed by depression, dyspnea, and shock. Three of 6 animals died by 52 hr. The most striking gross lesion in all 6 monkeys was diffuse severe pulmonary edema. Histologically, edema fluid was present within the peribronchiolar, peribronchial, and perivascular interstitium, alveolar septa, and alveoli. The adventitia of pulmonary vessels was infiltrated by lymphocytes, macrophages, and fewer neutrophils. Numerous large lymphocytes with occasional mitotic figures were within pulmonary vessels, often occluding alveolar capillaries. These cells were strongly immunoreactive with monoclonal antibodies against CD3, establishing them as T cells. Ultrastructurally, endothelial cell junctions were intact, and endothelial cells and type I pneumocytes contained numerous pinocytotic vesicles. Alveolar septal interstitial spaces were expanded by edema. The mechanism of these SEB-induced pulmonary lesions was not determined. We hypothesize that cytokine production by activated T cells may have caused vascular permeability changes leading to widespread pulmonary edema and shock.

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

“…Lung lesions reported after intratracheal administration of SEB to SCID mice (12,34) were characterized as interstitial pneumonia with infiltration of mononuclear cells into alveolar septal walls and periarterial spaces. Similar changes were observed in C3H/HeJ mice primed with actinomycin D and treated intraperitoneally with SEB (9), as well as in rhesus monkeys exposed to aerosolized SEB (17,22). Initial activation followed by depletion of BALT and other lymphoid tissues was a most characteristic finding.…”

Suppression of Staphylococcal Enterotoxin B-induced Toxicity by a Nuclear Import Inhibitor

“…These high-risk community-acquired infections, which may lead to NMTSS, occur with increasing frequency as compared with the greater than 2 million hospitalacquired infections recorded annually in the United States (3,4). Strikingly, SEB induces a fatal respiratory distress syndrome in non-human primates, suggesting its potential use as a bioweapon on the battlefield or in mass civilian settings (5,6). Potential air-borne, water-borne, and food-borne use of SEB led to its designation by the United States Centers for Disease Control as a category B agent.…”

“…The resulting intercellular "synapse" generated by SEB engagement leads to excessive production of the inflammatory cytokines tumor necrosis factor ␣ (TNF␣), interferon ␥ (IFN␥), interleukin (IL)-1␤, IL-2, and IL-6. T cell-produced inflammatory cytokines contribute to massive vascular injury, organ failure, and depending on the mode of exposure potentially lethal respiratory distress syndrome or toxic shock (1,2,5,6). Active immunization prior to SEB exposure and passive immunization immediately after exposure are not readily available (6).…”

Transcriptional response signature of human lymphoid cells to staphylococcal enterotoxin B

“…3 Recent studies illustrate extensive perivascular edema in numerous organs. 4 Vascular leakage and pathological hypotension eventually lead to irreversible shock, multiorgan failure and death at about 44-66 h postexposure in nonhuman primates (NHP). 5 The molecular sequence of events induced by these toxins include a massive cytokine release, and strategies that show a limited success at o4 h postexposure.…”