title: Ricin crosses polarized human intestinal cells and intestines of ricin-gavaged mice without evident damage and then disseminates to mouse kidneys.
abstract: Ricin is a potent toxin found in the beans of Ricinus communis and is often lethal for animals and humans when aerosolized or injected and causes significant morbidity and occasional death when ingested. Ricin has been proposed as a bioweapon because of its lethal properties, environmental stability, and accessibility. In oral intoxication, the process by which the toxin transits across intestinal mucosa is not completely understood. To address this question, we assessed the impact of ricin on the gastrointestinal tract and organs of mice after dissemination of toxin from the gut. We first showed that ricin adhered in a specific pattern to human small bowel intestinal sections, the site within the mouse gut in which a variable degree of damage has been reported by others. We then monitored the movement of ricin across polarized human HCT-8 intestinal monolayers grown in transwell inserts and in HCT-8 cell organoids. We observed that, in both systems, ricin trafficked through the cells without apparent damage until 24 hours post intoxication. We delivered a lethal dose of purified fluorescently-labeled ricin to mice by oral gavage and followed transit of the toxin from the gastrointestinal tracts to the internal organs by in vivo imaging of whole animals over time and ex vivo imaging of organs at various time points. In addition, we harvested organs from unlabeled ricin-gavaged mice and assessed them for the presence of ricin and for histological damage. Finally, we compared serum chemistry values from buffer-treated versus ricin-intoxicated animals. We conclude that ricin transverses human intestinal cells and mouse intestinal cells in situ prior to any indication of enterocyte damage and that ricin rapidly reaches the kidneys of intoxicated mice. We also propose that mice intoxicated orally with ricin likely die from distributive shock.
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
authors.forename: Alyssa D
authors.initials: AD
authors.lastname: Flora
authors.forename: Louise D
authors.initials: LD
authors.lastname: Teel
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: James F
authors.initials: JF
authors.lastname: Sinclair
authors.forename: Angela R
authors.initials: AR
authors.lastname: Melton-Celsa
authors.forename: Alison D
authors.initials: AD
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D005455:Fluorescent Antibody Technique; D006801:Humans; D007422:Intestines / Q000187:drug effects*; D007668:Kidney / Q000473:pathology*; D008297:Male; D051379:Mice; D012276:Ricin / Q000633:toxicity*; D014709:Vero Cells
chemical_list: D012276:Ricin