Sensitization of Airway Epithelial Cells to Toxin-Induced Death by TNF Superfamily Cytokines

Reynolds-Peterson, Claire; Ehrbar, Dylan; McHale, Susanne M; LaRocca, Timothy J.; Mantis, Nicholas J.

doi:10.1007/978-1-0716-1130-2_2

Cited by 3 publications

(5 citation statements)

References 23 publications

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“… 33 , 34 On the other end of the spectrum, A549 cells are reportedly relatively insensitive to RT, unless sensitized with TNF‐α or TRAIL. 17 , 18 , 31 The A549 cell line is derived from an alveolar cell carcinoma and exhibits characteristics of alveolar type II epithelium (ATII). 35 …”

Section: Resultsmentioning

confidence: 99%

“…A detailed protocol for the CellTiter‐Glo viability assay, including combinatorial treatment as performed in herein, has been published elsewhere. 31 THP‐1 cells were seeded at 2.5 × 10 3 cells per well in 96‐well plates and differentiated with PMA in the assay plates as described above. THP‐1 cells were exposed to ricin for 2 h and were allowed 18–22 h of recovery prior to assessing viability.…”

Section: Methodsmentioning

confidence: 99%

“…A detailed protocol for the Cell TiterGlo viability assay, including combinatorial treatment as performed in herein, has been published elsewhere (31). THP-1 cells were seeded at 2.5…”

Section: Cytotoxicity and Protein Synthesis Assaysmentioning

confidence: 99%

“…33,34 On the other end of the spectrum, A549 cells are reportedly relatively insensitive to RT, unless sensitized with TNF-α or TRAIL. 17,18,31 The A549 cell line is derived from an alveolar cell carcinoma and exhibits characteristics of alveolar type II epithelium (ATII). 35 To compare the sensitivity of the two aforementioned cell types to RT at near identical parameters, PMAdifferentiated THP-1 (dTHP-1) cells and A549 cells were each exposed to a range of toxin concentrations (0.5-500 ng/ml) for 4 h, washed, and then examined for cell viability 24 h later.…”

Section: Differential Sensitivity Of A549 and Thp-1 Cells To Rtmentioning

confidence: 99%

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Differential ER stress as a driver of cell fate following ricin toxin exposure

Peterson-Reynolds

Mantis

2021

FASEB BioAdvances

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Acute respiratory distress syndrome (ARDS) is a lifethreatening complication brought about by a variety of insults ranging from physical injury to viral infection to toxin exposure. One such provocateur is ricin, a type II ribosome-inactivating protein (RIP) or ribotoxin found in castor beans (Ricinus communis). 1-3 Ricin's B subunit (RTB) is a Gal/GalNAc-specific lectin that adheres to glycoproteins and glycolipids on cell surfaces and promotes

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…A detailed protocol for the Cell TiterGlo viability assay, including combinatorial treatment as performed in herein, has been published elsewhere (31). THP-1 cells were seeded at 2.5…”

Section: Cytotoxicity and Protein Synthesis Assaysmentioning

confidence: 99%

Section: Differential Sensitivity Of A549 and Thp-1 Cells To Rtmentioning

confidence: 99%

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Differential ER stress as a driver of cell fate following ricin toxin exposure

Peterson-Reynolds

Mantis

2021

FASEB BioAdvances

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“…Disease severity and lung permeability coincide with elevated levels of pro-inflammatory cytokines such as IL-6, IL-1, and tumor necrosis factor alpha (TNF-α) in sera and bronchoalveolar lavages (BAL) 10,[13][14][15] . Airway damage may be further exacerbated by TNF-α and its family members, which render lung epithelial cells hyper-sensitive to the effects of RT [16][17][18] .…”

Section: Introductionmentioning

confidence: 99%

Serum antibody profiling identifies vaccine-induced correlates of protection against aerosolized ricin toxin in rhesus macaques

et al. 2022

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Inhalation of the biothreat agent, ricin toxin (RT), provokes a localized inflammatory response associated with pulmonary congestion, edema, neutrophil infiltration, and severe acute respiratory distress. The extreme toxicity of RT is the result of the toxin’s B chain (RTB) promoting rapid uptake into alveolar macrophages and lung epithelial cells, coupled with the A chain’s (RTA) potent ribosome-inactivating properties. We previously reported that intramuscular vaccination of rhesus macaques with a lyophilized, alum-adsorbed recombinant RTA subunit vaccine (RiVax®) was sufficient to confer protection against a lethal dose of aerosolized RT. That study implicated RT-specific serum IgG, toxin-neutralizing activity (TNA), and epitope-specific responses as being associated with immunity. However, it was not possible to define actual correlates of protection (COP) because all vaccinated animals survived the RT challenge. We addressed the issue of COP in the current study, by vaccinating groups of rhesus macaques with RiVax® following the previously determined protective regimen (100 µg on study days 0, 30 and 60) or one of two anticipated suboptimal regimens (100 µg on study days 30 and 60; 35 µg on study days 0, 30, and 60). Two unvaccinated animals served as controls. The animals were challenged with ~5 × LD50s of aerosolized RT on study day 110. We report that all vaccinated animals seroconverted prior to RT challenge, with the majority also having measurable TNA, although neither antibody levels nor TNA reached statistical significance with regard to a correlation with protection. By contrast, survival correlated with pre-challenge, epitope-specific serum IgG levels, derived from a competitive sandwich ELISA using a panel of toxin-neutralizing monoclonal antibodies directed against distinct epitopes on RiVax®. The identification of a species-neutral, competitive ELISA that correlates with vaccine-induced protection against RT in nonhuman represents an important advance in the development of medical countermeasures (MCM) against a persistent biothreat.

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Durable Immunity to Ricin Toxin Elicited by Intranasally Administered Monoclonal Antibody–Based Immune Complexes

et al. 2022

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Inhalation of ricin toxin (RT) elicits profuse inflammation and cell death within the upper and lower airways, ultimately culminating in acute respiratory distress syndrome. We previously reported that the effects of pulmonary RT exposure in mice are nullified by intranasal administration of an mAb mixture consisting of PB10, directed against ricin’s enzymatic subunit (RTA), and SylH3, directed against ricin’s binding subunit (RTB). We now report that delivery of PB10 and SylH3 as an RT–mAb immune complex (RIC) to mice by the intranasal or i.p. routes stimulates the rapid onset of RT-specific serum IgG that persists for months. RIC administration also induced high-titer, toxin-neutralizing Abs. Moreover, RIC-treated mice were immune to a subsequent 5 × LD50 RT challenge on days 30 or 90. Intranasal RIC administration was more effective than i.p. delivery at rendering mice immune to intranasal RT exposure. Finally, we found that the onset of RT-specific serum IgG following RIC delivery was independent of FcγR engagement, as revealed through FcγR knockout mice and RICs generated with PB10/SylH3 LALA (leucine to alanine) derivatives. In conclusion, a single dose of RICs given intranasally to mice was sufficient to stimulate durable protective immunity to RT by an FcγR-independent pathway.

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Sensitization of Airway Epithelial Cells to Toxin-Induced Death by TNF Superfamily Cytokines

Cited by 3 publications

References 23 publications

Differential ER stress as a driver of cell fate following ricin toxin exposure

Differential ER stress as a driver of cell fate following ricin toxin exposure

Serum antibody profiling identifies vaccine-induced correlates of protection against aerosolized ricin toxin in rhesus macaques

Durable Immunity to Ricin Toxin Elicited by Intranasally Administered Monoclonal Antibody–Based Immune Complexes

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