Abstract
Abrin and ricin are potent AB toxins, which are considered biological threats. To date, there are no approved treatments against abrin or ricin intoxications. Previously, we showed that the administration of polyclonal anti-abrin antibodies to mice that were intranasally exposed to abrin, even very late post-exposure, conferred an exceedingly high-level of protection, while following ricin intoxication, similar treatment with anti-ricin antibodies resulted in negligible survival rates. To probe this unexpected difference in protection ability, we first examined whether the efficient anti-abrin-induced protection was due to neutralization of the A-subunit responsible for the catalytic effect, or of the B-subunit, which enables binding/internalization, by evaluating the protection conferred by antibodies directed against one of the two subunits. To this end, we generated and immunized rabbits with chimeric toxins containing a single abrin subunit, AabrinBricin in which abrin A-subunit was linked to ricin B-subunit, and AricinBabrin in which ricin A-subunit is linked to abrin B-subunit. Here, we show that antibodies raised against either AabrinBricin or AricinBabrin conferred exceptionally high protection levels to mice following intranasal exposure to a a lethal dose of abrin, suggesting that the high level of protection conferred by anti-abrin antibodies is not related to the neutralization of a particular subunit.
Highlights
Abrin and ricin, plant toxins derived from rosary peas (Abrus precatorius) and castor bean plant (Ricinus communis), respectively, belong to the type 2 ribosome inactivating (RIP-2) group of proteins.The heterodimeric glycoprotein of both toxins comprises subunit A, carrying the enzymatic activity of the toxin, and subunit B, which is a lectin that binds to eukaryotic cell surfaces via galactose residues and mediates toxin internalization [1]
Export of the abrin monomeric A-subunit from the endoplasmic reticulum (ER) into the cytosol relies on the fact that following toxin reduction in the ER, the isolated A-chain is identified as a misfolded protein, thereby allowing its retrieval to the cytosol via the ER degradation pathway [15,16]
MAbs directed against Aabrin -abrus precatorius agglutinin (APA) chimeric toxin
Summary
Plant toxins derived from rosary peas (Abrus precatorius) and castor bean plant (Ricinus communis), respectively, belong to the type 2 ribosome inactivating (RIP-2) group of proteins.The heterodimeric glycoprotein of both toxins comprises subunit A, carrying the enzymatic activity of the toxin, and subunit B, which is a lectin that binds to eukaryotic cell surfaces via galactose residues and mediates toxin internalization [1]. Upon entry to the cytosol, the A-subunits of both ricin and abrin inactivate ribosomes irreversibly by site-specific depurination of a specific adenine nucleotide within the 28S rRNA, thereby precipitating cessation of cellular protein synthesis [2]. Due to their high availability, ease of preparation and high toxicity, ricin and abrin are considered potential bioterror agents and are classified as Category B agents by the US Center for Disease Control and Prevention (CDC). There are no approved post-exposure therapeutic countermeasures for either toxin. The clinical manifestation following intranasal exposure of mice to these
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