Clinical and Pathological Findings Associated with Aerosol Exposure of Macaques to Ricin Toxin

Abstract

Ricin is a potential bioweapon that could be used against civilian and military personnel. Aerosol exposure is the most likely route of contact to ricin toxin that will result in the most severe toxicity. Early recognition of ricin exposure is essential if specific antidotes are to be applied. Initial diagnosis will most likely be syndromic, i.e., fitting clinical and laboratory signs into a pattern which then will guide the choice of more specific diagnostic assays and therapeutic interventions. We have studied the pathology of ricin toxin in rhesus macaques exposed to lethal and sublethal ricin aerosols. Animals exposed to lethal ricin aerosols were followed clinically using telemetry, by clinical laboratory analyses and by post-mortem examination. Animals exposed to lethal aerosolized ricin developed fever associated with thermal instability, tachycardia, and dyspnea. In the peripheral blood a marked neutrophilia (without immature bands) developed at 24 h. This was accompanied by an increase in monocytes, but depletion of lymphocytes. Red cell indices indicated hemoconcentration, as did serum chemistries, with modest increases in sodium and blood urea nitrogen (BUN). Serum albumin was strikingly decreased. These observations are consistent with the pathological observations of fluid shifts to the lungs, in the form of hemorrhages, inflammatory exudates, and tissue edema. In macaques exposed to sublethal aerosols of ricin, late pathologic consequences included chronic pulmonary fibrosis, likely mediated by M2 macrophages. Early administration of supportive therapy, specific antidotes after exposure or vaccines prior to exposure have the potential to favorably alter this outcome.

High-Resolution Epitope Positioning of a Large Collection of Neutralizing and Nonneutralizing Single-Domain Antibodies on the Enzymatic and Binding Subunits of Ricin Toxin

“…Ricin is classified as a category B biothreat agent by the Centers for Disease Control and Prevention (CDC) because of its potential, when delivered via aerosol, to induce severe lung inflammation and tissue damage (9,10). Concerns over ricin's possible use as a biothreat agent stem from the fact that the toxin is relatively easy to procure from its natural source, castor beans (Ricinus communis), as well as from its extreme toxicity following inhalation or injection (11).…”

Recent advances in the development of vaccines against ricin

“…Clinical laboratory analyses in control animals showed hemoconcentration, which correlated with fluid shifts from the blood to the lungs and were associated with histologic evidence of pulmonary inflammation. 20 In contrast, immunized animals showed no evidence of hemoconcentration or fluid shifts, as exemplified by hematocrits. There were no changes in the numbers of RBCs, hemoglobin concentrations, or blood urea nitrogen such as has been observed in control animals.…”

“…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.…”

High-Definition Mapping of Four Spatially Distinct Neutralizing Epitope Clusters on RiVax, a Candidate Ricin Toxin Subunit Vaccine

“…At the tissue level, particularly in the context of the lung, ricin induces severe inflammation with a marked influx of neutrophils, alveolar edema, and hemorrhages (8,9). Nonhuman primates (rhesus macaques) exposed to ricin by aerosol succumb to the effects of the toxin within 24 to 52 h (8,10). At this time, medical intervention following ricin exposure is strictly supportive (11).…”

“…Ricin's binding subunit, ricin toxin B subunit (RTB), is a galactose/N-acetyl galactosamine (Gal/GalNAc)-specific lectin that promotes toxin entry into mammalian cells, while ricin's enzymatic subunit, RTA, is an RNA N-glycosidase (EC 3.2.2.22) that, when successfully delivered into the cytoplasm, cleaves the sarcin-ricin loop (SRL) of 28S rRNA, thereby stalling ribosome translocation (6,7). At the tissue level, particularly in the context of the lung, ricin induces severe inflammation with a marked influx of neutrophils, alveolar edema, and hemorrhages (8,9). Nonhuman primates (rhesus macaques) exposed to ricin by aerosol succumb to the effects of the toxin within 24 to 52 h (8,10).…”