An intranasally administered monoclonal antibody cocktail abrogates ricin toxin-induced pulmonary tissue damage and inflammation

Ricin toxin, a plant-derived, mannosylated glycoprotein, elicits an incapacitating and potentially lethal inflammatory response in the airways following inhalation. Uptake of ricin by alveolar macrophages (AM) and other pulmonary cell types occurs via two parallel pathways: one mediated by ricin’s B...

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Main Authors: Yinghui Rong, Fernando J. Torres-Velez, Dylan Ehrbar, Jennifer Doering, Renjie Song, Nicholas J. Mantis
Format: Article
Language:English
Published: Taylor & Francis Group 2020-04-01
Series:Human Vaccines & Immunotherapeutics
Subjects:
Online Access:http://dx.doi.org/10.1080/21645515.2019.1664243
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author Yinghui Rong
Fernando J. Torres-Velez
Dylan Ehrbar
Jennifer Doering
Renjie Song
Nicholas J. Mantis
author_facet Yinghui Rong
Fernando J. Torres-Velez
Dylan Ehrbar
Jennifer Doering
Renjie Song
Nicholas J. Mantis
author_sort Yinghui Rong
collection DOAJ
description Ricin toxin, a plant-derived, mannosylated glycoprotein, elicits an incapacitating and potentially lethal inflammatory response in the airways following inhalation. Uptake of ricin by alveolar macrophages (AM) and other pulmonary cell types occurs via two parallel pathways: one mediated by ricin’s B subunit (RTB), a galactose-specific lectin, and one mediated by the mannose receptor (MR;CD206). Ricin’s A subunit (RTA) is a ribosome-inactivating protein that triggers apoptosis in mammalian cells. It was recently reported that a single monoclonal antibody (MAb), PB10, directed against an immunodominant epitope on RTA and administered intravenously, was able to rescue Rhesus macaques from lethal aerosol dose of ricin. In this study, we now demonstrate in mice that the effectiveness PB10 is significantly improved when combined with a second MAb, SylH3, against RTB. Mice treated with PB10 alone survived lethal-dose intranasal ricin challenge, but experienced significant weight loss, moderate pulmonary inflammation (e.g., elevated IL-1 and IL-6 levels, PMN influx), and apoptosis of lung macrophages. In contrast, mice treated with the PB10/SylH3 cocktail were essentially impervious to pulmonary ricin toxin exposure, as evidenced by no weight loss, no change in local IL-1 and IL-6 levels, retention of lung macrophages, and a significant dampening of PMN recruitment into the bronchoalveolar lavage (BAL) fluids. The PB10/SylH3 cocktail only marginally reduced ricin binding to target cells in the BAL, suggesting that the antibody mixture neutralizes ricin by interfering with one or more steps in the RTB- and MR-dependent uptake pathways.
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spelling doaj.art-a155ae3ee1894daca689a4eb8cc9ba1e2023-09-22T08:45:33ZengTaylor & Francis GroupHuman Vaccines & Immunotherapeutics2164-55152164-554X2020-04-0116479380710.1080/21645515.2019.16642431664243An intranasally administered monoclonal antibody cocktail abrogates ricin toxin-induced pulmonary tissue damage and inflammationYinghui Rong0Fernando J. Torres-Velez1Dylan Ehrbar2Jennifer Doering3Renjie Song4Nicholas J. Mantis5Division of Infectious Disease, Wadsworth CenterDivision of Infectious Disease, Wadsworth CenterDivision of Infectious Disease, Wadsworth CenterDivision of Infectious Disease, Wadsworth CenterDivision of Infectious Disease, Wadsworth CenterDivision of Infectious Disease, Wadsworth CenterRicin toxin, a plant-derived, mannosylated glycoprotein, elicits an incapacitating and potentially lethal inflammatory response in the airways following inhalation. Uptake of ricin by alveolar macrophages (AM) and other pulmonary cell types occurs via two parallel pathways: one mediated by ricin’s B subunit (RTB), a galactose-specific lectin, and one mediated by the mannose receptor (MR;CD206). Ricin’s A subunit (RTA) is a ribosome-inactivating protein that triggers apoptosis in mammalian cells. It was recently reported that a single monoclonal antibody (MAb), PB10, directed against an immunodominant epitope on RTA and administered intravenously, was able to rescue Rhesus macaques from lethal aerosol dose of ricin. In this study, we now demonstrate in mice that the effectiveness PB10 is significantly improved when combined with a second MAb, SylH3, against RTB. Mice treated with PB10 alone survived lethal-dose intranasal ricin challenge, but experienced significant weight loss, moderate pulmonary inflammation (e.g., elevated IL-1 and IL-6 levels, PMN influx), and apoptosis of lung macrophages. In contrast, mice treated with the PB10/SylH3 cocktail were essentially impervious to pulmonary ricin toxin exposure, as evidenced by no weight loss, no change in local IL-1 and IL-6 levels, retention of lung macrophages, and a significant dampening of PMN recruitment into the bronchoalveolar lavage (BAL) fluids. The PB10/SylH3 cocktail only marginally reduced ricin binding to target cells in the BAL, suggesting that the antibody mixture neutralizes ricin by interfering with one or more steps in the RTB- and MR-dependent uptake pathways.http://dx.doi.org/10.1080/21645515.2019.1664243toxinlunginflammationantibodybiodefense
spellingShingle Yinghui Rong
Fernando J. Torres-Velez
Dylan Ehrbar
Jennifer Doering
Renjie Song
Nicholas J. Mantis
An intranasally administered monoclonal antibody cocktail abrogates ricin toxin-induced pulmonary tissue damage and inflammation
Human Vaccines & Immunotherapeutics
toxin
lung
inflammation
antibody
biodefense
title An intranasally administered monoclonal antibody cocktail abrogates ricin toxin-induced pulmonary tissue damage and inflammation
title_full An intranasally administered monoclonal antibody cocktail abrogates ricin toxin-induced pulmonary tissue damage and inflammation
title_fullStr An intranasally administered monoclonal antibody cocktail abrogates ricin toxin-induced pulmonary tissue damage and inflammation
title_full_unstemmed An intranasally administered monoclonal antibody cocktail abrogates ricin toxin-induced pulmonary tissue damage and inflammation
title_short An intranasally administered monoclonal antibody cocktail abrogates ricin toxin-induced pulmonary tissue damage and inflammation
title_sort intranasally administered monoclonal antibody cocktail abrogates ricin toxin induced pulmonary tissue damage and inflammation
topic toxin
lung
inflammation
antibody
biodefense
url http://dx.doi.org/10.1080/21645515.2019.1664243
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