Pathology of Lethal and Sublethal Doses of Aerosolized Ricin in Rhesus Macaques

Abstract

Ricin toxin, a type 2 ribosome inactivating protein and a category B bioterrorism agent, is produced from the seeds of castor oil plant (Ricinus communis). Chronic pathological changes in survivors of aerosolized ricin exposure have not been reported in primates. Here we compare and contrast the pathological changes manifested between rhesus macaques (RM) that succumbed to lethal dose of ricin (Group I) and survivor RM exposed to low dose of ricin (group II). All animals in group I exhibited severe diffuse, necrotizing bronchiolitis and alveolitis with fibrinopurulent bronchointerstitial pneumonia, massive alveolar, perivascular and peribronchial/bronchiolar edema with hemorrhage and necropurulent and hemorrhagic tracheobronchial lymphadenitis. All animals from groups II had multifocal, fibrosing interstitial pneumonia with prominent alveolar histiocytosis and type II pneumocyte hyperplasia. Subacute changes like infiltration by lymphocytes and plasma cells and persistence of edematous fluid were occasionally present in lung and tracheobronchial lymph nodes. The changes appear to be a continuum wherein the inflammatory response shifts from an acute to subacute/chronic reparative process if the animals can survive the initial insult.

Recent advances in the development of vaccines against ricin

“…Over the past few years, studies of RT aerosols in rhesus macaque (Macaca mulatta) have suggested that these animals are a suitable model for vaccine development. 2 Upon aerosol exposure to supra-lethal doses of RT, macaques develop massive pulmonary edema with necrotizing alveolitis that mainly affects the lower respiratory tract from terminal bronchioles to alveoli.…”

“…Yet we also know that much of the syndrome associated with exposure to RT and other toxins is due to an acute inflammatory response. 2,[20][21][22] It is not yet known how antibodies, which are themselves proinflammatory, block the proinflammatory activity of the toxin, rather than enhancing it. We can partially address this question by comparing inflammatory responses in immunized macaques with those observed in the controls.…”

“…Indeed, within hours of aerosol exposure of non-human primates (NHPs) and rodents, RT causes clinical symptoms that are associated with epithelial necrosis, multifocal hemorrhagic edema and death within 24-36 hours. 2,3 By inhalation, RT toxicity onset is rapid and irreversible, with a lethal dose in laboratory animals, including rhesus macaques, of~5 mg/kg. The lethal dose of aerosolized RT extrapolated to humans is approximately 350 mg of inhaled RT for a 70 kg individual.…”

“…The dramatic and severe pathologies associated with aerosol exposure are primarily confined to the lung and associated parenchyma although damage to the gut has also been observed after oral ingestion. 2 RT is designated by the CDC and NIH as a select agent Class B Biothreat. RT is also a significant concern to the US military because of its potential deployment as a bioweapon.…”

Modeling of toxin–antibody interaction and toxin transport toward the endoplasmic reticulum

“…Ricin poisoning can cause severe tissue damage, inflammatory reactions, and blockage of protein synthesis, and thus result in cell death [1,2]. In spite of intensive biomedical research, no treatment is at present available for ricin poisoning [3].…”