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

Rong, Yinghui; Westfall, Jennifer; Ehrbar, Dylan; LaRocca, Timothy J.; Mantis, Nicholas J.

doi:10.1128/msphere.00399-18

Cited by 10 publications

(22 citation statements)

References 57 publications

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“…[10][11][12] Local damage is further exacerbated by TNF-α and its family members like TRAIL, which render lung epithelial cells hyper-sensitive to the effects of RT, as evidenced by augmented (>300 fold) secretion of IL-6 and other proinflammatory cytokines, as well as a lower threshold to elicit PCD. 13 This positive feedback loop likely contributes to the rapid onset of acute lung injury that is observed in Rhesus macaques following RT aerosol exposure. 8,11 Given the rapid onset of RT toxicity following aerosol exposure, the opportunity to intervene and reverse the effects of lethal dose RT exposure is likely to be on the order of hours.…”

Section: Introductionmentioning

confidence: 99%

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Passive immunization with an extended half-life monoclonal antibody protects Rhesus macaques against aerosolized ricin toxin

et al. 2020

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Inhalation of ricin toxin (RT), a Category B biothreat agent, provokes an acute respiratory distress syndrome marked by proinflammatory cytokine and chemokine production, neutrophilic exudate, and pulmonary edema. The severity of RT exposure is attributed to the tropism of the toxin's B subunit (RTB) for alveolar macrophages and airway epithelial cells, coupled with the extraordinarily potent ribosome-inactivating properties of the toxin's enzymatic subunit (RTA). While there are currently no vaccines or treatments approved to prevent RT intoxication, we recently described a humanized anti-RTA IgG 1 MAb, huPB10, that was able to rescue non-human primates (NHPs) from lethal dose RT aerosol challenge if administered by intravenous (IV) infusion within hours of toxin exposure. We have now engineered an extended serum half-life variant of that MAb, huPB10-LS, and evaluated it as a pre-exposure prophylactic. Five Rhesus macaques that received a single intravenous infusion (25 mg/kg) of huPB10-LS survived a lethal dose aerosol RT challenge 28 days later, whereas three control animals succumbed to RT intoxication within 48 h. The huPB10-LS treated animals remained clinically normal in the hours and days following toxin insult, suggesting that pre-existing antibody levels were sufficient to neutralize RT locally. Moreover, pro-inflammatory markers in sera and BAL fluids collected 24 h following RT challenge were significantly dampened in huPB10-LS treated animals, as compared to controls. Finally, we found that all five surviving animals, within days after RT exposure, had anti-RT serum IgG titers against epitopes other than huPB10-LS, indicative of active immunization by residual RT and/or RT-immune complexes.

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Section: Introductionmentioning

confidence: 99%

“…npj Vaccines (2020)13 Published in partnership with the Sealy Center for Vaccine Development1234567890():,;…”

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confidence: 99%

Passive immunization with an extended half-life monoclonal antibody protects Rhesus macaques against aerosolized ricin toxin

et al. 2020

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“…Previously, we reported that the cytokine TNF-α related apoptosis-inducing ligand (TRAIL) modulates the toxicity of ricin as well as the host inflammatory response to this toxin [20]. In particular, we demonstrated that addition of TRAIL enhanced the death of Calu-3 human lung epithelial cells in a caspase-dependent manner and evoked an inflammatory response dominated by IL-6 [20].…”

Section: Introductionmentioning

confidence: 99%

TNF Family Cytokines Induce Distinct Cell Death Modalities in the A549 Human Lung Epithelial Cell Line when Administered in Combination with Ricin Toxin

Kempen

McCaig

Parker

et al. 2019

Toxins

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Ricin is a member of the ribosome-inactivating protein (RIP) family of toxins and is classified as a biothreat agent by the Centers for Disease Control and Prevention (CDC). Inhalation, the most potent route of toxicity, triggers an acute respiratory distress-like syndrome that coincides with near complete destruction of the lung epithelium. We previously demonstrated that the TNF-related apoptosis-inducing ligand (TRAIL; CD253) sensitizes human lung epithelial cells to ricin-induced death. Here, we report that ricin/TRAIL-mediated cell death occurs via apoptosis and involves caspases -3, -7, -8, and -9, but not caspase-6. In addition, we show that two other TNF family members, TNF-α and Fas ligand (FasL), also sensitize human lung epithelial cells to ricin-induced death. While ricin/TNF-α- and ricin/FasL-mediated killing of A549 cells was inhibited by the pan-caspase inhibitor, zVAD-fmk, evidence suggests that these pathways were not caspase-dependent apoptosis. We also ruled out necroptosis and pyroptosis. Rather, the combination of ricin plus TNF-α or FasL induced cathepsin-dependent cell death, as evidenced by the use of several pharmacologic inhibitors. We postulate that the effects of zVAD-fmk were due to the molecule’s known off-target effects on cathepsin activity. This work demonstrates that ricin-induced lung epithelial cell killing occurs by distinct cell death pathways dependent on the presence of different sensitizing cytokines, TRAIL, TNF-α, or FasL.

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“…Alveolar macrophages are particularly sensitive to RT and their numbers plummet within hours of toxin exposure [7,10,25]. Mucosal damage is exacerbated by TNF-α and its family members like TNF-related apoptosis-inducing ligand (TRAIL), which render lung epithelial cells hyper-sensitive to the effects of RT [9,26].…”

Section: Discussionmentioning

confidence: 99%

“…The underlying cause of death following pulmonary RT exposure is likely acute respiratory distress [3][4][5][6]. Alveolar macrophages (AM) are particularly susceptible to RT and are postulated to contribute to amplification of disease severity through the secretion of pro-inflammatory cytokines, which have the potential to sensitize airway epithelial cells to toxin-induced programmed cell death [7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

A Humanized Monoclonal Antibody Cocktail to Prevent Pulmonary Ricin Intoxication

Rong

Pauly

Guthals

et al. 2020

Toxins

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PB10 IgG1, a monoclonal antibody (MAb) directed against an immunodominant epitope on the enzymatic subunit (RTA) of ricin toxin (RT), has been shown to passively protect mice and non-human primates from an aerosolized lethal-dose RT challenge. However, it was recently demonstrated that the therapeutic efficacy of PB10 IgG1 is significantly improved when co-administered with a second MAb, SylH3, targeting RT’s binding subunit (RTB). Here we report that the PB10/SylH3 cocktail is also superior to PB10 alone when used as a pre-exposure prophylactic (PrEP) in a mouse model of intranasal RT challenge. The benefit of the PB10/SylH3 cocktail prompted us to engineer a humanized IgG1 version of SylH3 (huSylH3). The huPB10/huSylH3 cocktail proved highly efficacious in the mouse model, thereby opening the door to future testing in non-human primates.

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

Cited by 10 publications

References 57 publications

Passive immunization with an extended half-life monoclonal antibody protects Rhesus macaques against aerosolized ricin toxin

Passive immunization with an extended half-life monoclonal antibody protects Rhesus macaques against aerosolized ricin toxin

TNF Family Cytokines Induce Distinct Cell Death Modalities in the A549 Human Lung Epithelial Cell Line when Administered in Combination with Ricin Toxin

A Humanized Monoclonal Antibody Cocktail to Prevent Pulmonary Ricin Intoxication

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