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Recombinant Mucin-Type Fusion Proteins with a Gal alpha 1,3Gal Substitution as Clostridium difficile Toxin A Inhibitors

Journal article
Authors Reeja Maria Cherian
Chunsheng S. Jin
Jining Liu
Niclas G. Karlsson
Jan Holgersson
Published in Infection and Immunity
Volume 84
Issue 10
Pages 2842-2852
ISSN 0019-9567
Publication year 2016
Published at Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 2842-2852
Language en
Links dx.doi.org/10.1128/iai.00341-16
Keywords hamster ovary cells, carbohydrate interactions, binding domain, b, determinants, high avidity, receptor, enterotoxin, metronidazole, recognition, antibodies, Immunology, Infectious Diseases
Subject categories Infectious Medicine, Immunology in the medical area

Abstract

The capability of a recombinant mucin-like fusion protein, P-selectin glycoprotein ligand-1/mouse IgG2b (PSGL-1/mIgG2b), carrying Gal alpha 1,3Gal beta 1,4GlcNAc determinants to bind and inhibit Clostridium difficile toxin A (TcdA) was investigated. The fusion protein, produced by a glyco-engineered stable CHO-K1 cell line and designated C-PGC2, was purified by affinity and gel filtration chromatography from large-scale cultures. Liquid chromatography-mass spectrometry was used to characterize O-glycans released by reductive beta-elimination, and new diagnostic ions to distinguish Gal alpha 1,3Gal- from Gal alpha 1,4Gal-terminated O-glycans were identified. The C-PGC2 cell line, which was 20-fold more sensitive to TcdA than the wild-type CHO-K1, is proposed as a novel cell-based model for TcdA cytotoxicity and neutralization assays. The C-PGC2-produced fusion protein could competitively inhibit TcdA binding to rabbit erythrocytes, making it a high-efficiency inhibitor of the hemagglutination property of TcdA. The fusion protein also exhibited a moderate capability for neutralization of TcdA cytotoxicity in both C-PGC2 and CHO-K1 cells, the former with and the latter without cell surface Gal alpha 1,3Gal beta 1,4GlcNAc sequences. Future studies in animal models of C. difficile infection will reveal its TcdA-inhibitory effect and therapeutic potential in C. difficile-associated diseases.

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