Molecular Recognition of Brucella A and M Antigens Dissected by Synthetic Oligosaccharide Glycoconjugates Leads to a Disaccharide Diagnostic for Brucellosis

被引:33
作者
Ganesh, N. Vijaya [1 ]
Sadowska, Joanna M. [1 ]
Sarkar, Susmita [1 ]
Howells, Laurence [2 ]
McGiven, John [2 ]
Bundle, David R. [1 ]
机构
[1] Univ Alberta, Dept Chem, Edmonton, AB T6G 2G2, Canada
[2] Anim Hlth & Vet Labs Agcy, Dept Bacteriol, OIE Brucellosis Reference Ctr, FAO WHO Collaborating Ctr Brucellosis, Addlestone KT15 3NB, Surrey, England
基金
加拿大自然科学与工程研究理事会;
关键词
YERSINIA-ENTEROCOLITICA; FORMIC ANHYDRIDE; O-ANTIGENS; ABORTUS; LIPOPOLYSACCHARIDE; DETERMINANTS; MELITENSIS; O-9; 4,6-DIDEOXY-4-FORMAMIDO-ALPHA-D-MANNOSE; PENTASACCHARIDE;
D O I
10.1021/ja5081184
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The cell wall O-polysaccharides of pathogenic Brucella species are homopolymers of the rare sugar 4,6-dideoxy-4-formamido-alpha-D-mannopyranose. Despite the apparent simplicity of the polysaccharide it appears to be a "block copolymer" composed of A and M polysaccharide sequences expressed as a single molecule. The simultaneous presence of both in the cell wall has complicated the understanding of the molecular recognition of these antigens by antibodies present in the serum of infected animals and humans and by monoclonal antibodies. Since presumptive diagnosis of brucellosis, a serious disease in domestic livestock, wild animals, and humans, is based on detection of these antibodies it is important to separate the two antigenic epitopes, one of which is also found in other bacteria. Chemical synthesis provides the only means to achieve this outcome. A series of six oligosaccharides from di to hexasaccharides 1-6 were synthesized and conjugated to proteins to provide glycoconjugate antigens and conjugate vaccines. These chemically defined antigens identified the M antigenic determinant and provided a structural basis for understanding the fine specificity of monoclonal and polyclonal antibodies that bind the M antigen. This resulted in the discovery of a disaccharide that shows considerable potential as an unambiguous diagnostic antigen for detecting brucellosis in humans and animals and two hexasaccharide conjugate vaccine candidates that produce high levels of O-polysaccharide specific antibodies in mice.
引用
收藏
页码:16260 / 16269
页数:10
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