Beyond the Dirty Dozen: A Proposed Methodology for Assessing Future Bioweapon Threats

Cieslak, Theodore J.; Kortepeter, Mark G.; Wojtyk, Ronald J; Jansen, Hugo-Jan; Reyes, Ricárdo; Smith, James O.; Panel, Nato Biological Medical Advisory

doi:10.1093/milmed/usx004

Cited by 33 publications

(30 citation statements)

References 13 publications

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“…Ricin toxin (RT) is considered a high priority biothreat agent by the Centers for Disease Control and Prevention (CDC), the US Department of Defense (DOD), and the North Atlantic Treaty Organization (NATO) due to its accessibility, stability, and high toxicity, especially by the aerosol route (1,2). In nonhuman primates (NHPs), inhalation of RT elicits the clinical equivalent of acute respiratory distress syndrome (ARDS), characterized by widespread apoptosis of alveolar macrophages, intraalveolar edema, neutrophilic infiltration, accumulation of proinflammatory cytokines, and fibrinous exudate (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Rescue of rhesus macaques from the lethality of aerosolized ricin toxin

et al. 2019

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Section: Introductionmentioning

confidence: 99%

Rescue of rhesus macaques from the lethality of aerosolized ricin toxin

et al. 2019

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“…Ricin toxin has been classified as a biological threat agent by the Centers for Disease Control and Prevention because of its extreme toxicity, the ease by which it can be procured from castor beans, and the absence of any available countermeasures . Continued concerns about ricin are underscored by a recent NATO Biomedical Advisory Council report that ranked ricin at the top of its list of agents with weaponization potential . Ricin is a ∼65 kDa heterodimeric glycoprotein consisting of 2 subunits, RTA and RTB, which are joined via a single disulfide bond.…”

Section: Introductionmentioning

confidence: 99%

Sensitivity of Kupffer cells and liver sinusoidal endothelial cells to ricin toxin and ricin toxin–Ab complexes

Mooney

Torres-Vélez

Doering

et al. 2019

Journal of Leukocyte Biology

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Ricin toxin is a plant‐derived, ribosome‐inactivating protein that is rapidly cleared from circulation by Kupffer cells (KCs) and liver sinusoidal endothelial cells (LSECs)—with fatal consequences. Rather than being inactivated, ricin evades normal degradative pathways and kills both KCs and LSECs with remarkable efficiency. Uptake of ricin by these 2 specialized cell types in the liver occurs by 2 parallel routes: a “lactose‐sensitive” pathway mediated by ricin's galactose/N‐acetylgalactosamine‐specific lectin subunit (RTB), and a “mannose‐sensitive” pathway mediated by the mannose receptor (MR; CD206) or other C‐type lectins capable of recognizing the mannose‐side chains displayed on ricin's A (RTA) and B subunits. In this report, we investigated the capacity of a collection of ricin‐specific mouse MAb and camelid single‐domain (VHH) antibodies to protect KCs and LSECs from ricin‐induced killing. In the case of KCs, individual MAbs against RTA or RTB afforded near complete protection against ricin in ex vivo and in vivo challenge studies. In contrast, individual MAbs or VHHs afforded little (<40%) or even no protection to LSECs against ricin‐induced death. Complete protection of LSECs was only achieved with MAb or VHH cocktails, with the most effective mixtures targeting RTA and RTB simultaneously. Although the exact mechanisms of protection of LSECs remain unknown, evidence indicates that the Ab cocktails exert their effects on the mannose‐sensitive uptake pathway without the need for Fcγ receptor involvement. In addition to advancing our understanding of how toxins and small immune complexes are processed by KCs and LSECs, our study has important implications for the development of Ab‐based therapies designed to prevent or treat ricin exposure should the toxin be weaponized.

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“…NATO’s Biomedical Advisory Council recently concluded that ricin ranks at the top of the list of potential biothreat agents, due in large part to the toxin’s extreme potency against numerous different cell types, as well as its capacity to be disseminated via aerosol 1 . In rodents, swine, and non-human primates (NHPs), inhalational ricin exposure evokes what is clinically equilavent to acute respiratory distress syndrome (ARDS) 2–4 In rodents and NHPs, the lethal dose 50 (LD 50 ) of ricin by aerosol is ~4 μg/kg 5–7 The hallmarks of ricin-induced lung damage include early onset of alveolar macrophage apoptosis (6-12 h) followed hours later by intra-alveolar edema, accumulation of inflammatory cytokines in the BAL, neutrophilic infiltration, and fibrinous exudate 5, 7–10 .…”

Section: Introductionmentioning

confidence: 99%

TRAIL (CD253) Sensitizes Human Airway Epithelial Cells to Toxin-Induced Cell Death

Rong

Westfall

Ehrbar

et al. 2018

Preprint

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Inhalation of ricin toxin is associated with the onset of acute respiratory distress syndrome (ARDS), characterized by hemorrhage, inflammatory exudates, and tissue edema, as well as the near complete destruction of the lung epithelium. Here we report that the Calu-3 human airway epithelial cell line is relatively impervious to the effects of ricin, with little evidence of cell death even upon exposure to microgram amounts of toxin. However, the addition of exogenous soluble TNF-Related Apoptosis Inducing Ligand (TRAIL; CD253) dramatically sensitized Calu-3 cells to ricin-induced apoptosis. Calu-3 cell killing in response to ricin and TRAIL was reduced upon the addition of caspase-8 and caspase-3/7 inhibitors, but not caspase 9 inhibitors, consistent with involvement of extrinsic apoptotic pathways in cell death. We employed nCounter Technology to define the transcriptional response of Calu-3 cells to ricin, TRAIL, and the combination of ricin plus TRAIL. An array of genes associated with inflammation-and cell death were significantly up regulated upon treatment with ricin toxin, and further amplified upon addition of TRAIL. Of particular note was IL-6, whose expression in Calu-3 cells increased 300-fold upon ricin treatment and more than 750-fold upon ricin and TRAIL treatment. IL-6 secretion by Calu-3 cells was confirmed by cytometric bead array. Based on these finding, we speculate that the severe airway epithelial cell damage observed in animal models following ricin exposure is a result of a positive feedback loop driven by pro-inflammatory cytokines like TRAIL and IL-6.

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Beyond the Dirty Dozen: A Proposed Methodology for Assessing Future Bioweapon Threats

Cited by 33 publications

References 13 publications

Rescue of rhesus macaques from the lethality of aerosolized ricin toxin

Rescue of rhesus macaques from the lethality of aerosolized ricin toxin

Sensitivity of Kupffer cells and liver sinusoidal endothelial cells to ricin toxin and ricin toxin–Ab complexes

TRAIL (CD253) Sensitizes Human Airway Epithelial Cells to Toxin-Induced Cell Death

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