The Role of Bacterial Lipooligosaccharides in the Pathogenesis of Human Disease.
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概要
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Lipooligosaccharides (LOS) are made by Gram negative bacteria that colonize mucosal surfaces other than those of the gut (1). These surface-exposed outer membrane organelles structurally resemble human cell membrane glycosphingolipids (GSL) more than they do the analogous lipopolysaccharides (LPS) of enteric Gram negative bacteria (1-3).One highly conserved LOS has the same lacto-N-neotetraose (LacNAcβ1→3Lac) glycose moiety (2, 4-6) as paragloboside-series GSL (7-9); other LOS glycose structures are shared with those of ganglio-(GalNAcβ1→3Gal-R), globo-(Galα1→4Lac-R, or P-series), and lacto-series (Lac-R) GSL (3, 10). By having the same surface glycose structures as human cells, these organisms can evade immune recognition (11-13). LOS biosynthesis is flexible. Lacto-N-neotetraose is formed by the β1→3 linkage of the disaccharide, lactosamine (LacNAc; Galβ1→4GlcNAc), to lactose (Lac; Galβ1→4Glc). The internal, or lactosyl, galactose (Gal) is a "toggle switch", or biosynthetic decision point: the glycose linked to it determines the structure of the mature LOS. A second Gal residue linked to it α1→4 (Pk globoside) stops further chain elongation, and the LOS terminates with the digalactoside. On the other hand, if glucosamine (GlcNAc) is added β1→3 to the lactosyl Gal, then a second Gal residue is added β1→4 to the GlcNAc residue to form the LacNAc disaccharide of lacto-N-neotetraose. The LacNAc terminal Gal is a second biosynthetic decision point: it may be unsubstituted (paraglobosyl) (2), adorned with sialic acid (sialoparaglobosyl) (14, 15), or substituted with galactosamine (GalNAc) in the β configuration (asialo-G3 gangliosyl) (6, 16). Sialylation of their LOS prevents lysis of the organisms by complement (immune lysis) (14, 17), retards their killing by polymorphonuclear leukocytes (PMNs) (18, 19) and enhances their ability to invade endocervical epithelial cells (20). Galactosaminylation provides a terminal GalNAc that binds bactericidal IgM molecules that are ubiquitous in human sera (21, 22). These antibodies initiate immune lysis of organisms that enter the blood stream (11) and thereby restrict colonization to the mucosa. Mucosal bacteria can vary LOS biosynthesis so as to express several different glycolipids that each mimic a different human GSL (3). LOS phase variation is quite rapid (10-3) (23, 24). This suggests that it may enable the organisms' to survive in different molecular environments, e. g., the mucosae of venereal consorts of different blood types, or the respiratory mucosa and subarachnoid space of a patient who develops meningitis. LOS phase shifts occur during the development of disease. A shift to Neisseria gonorrhoeae variants that make paraglobosyl, gangliosyl and higher Mr LOSs heralds the onset of symptomatic (? infectious) urethral leukorrhoea during gonococcal infection in men (24). Gonococci also must make paraglobosyl LOS that can be sialylated in order to invade endocervical epithelial cells (20). LOS biosynthetic genes currently are being identified. The "gene phase" of LOS biology opens up the possibility of discovering exactly how potentially pathogenic bacteria use their LOS to ensure their survival on various mucosal surfaces to cause disease in humans.
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