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Binding of pathogenic bacteria and bacterial toxins to host
cell surfaces is an essential step in establishing infection
in tissues and producing toxic effect. Glycosphingolipids on
cell surfaces are receptors for binding to cells.
There are many bacterial toxins that bind to ganglioside, an
acid glycosphingolipid, as the receptor on cell surface and invade
host cells. The best known of these is the cholera toxin, an
enterotoxin produced by Vibrio cholerae, and its specific cell
surface receptor was identified as ganglioside GM1. Cholera toxin
consists of a pentameric B subunit that binds to GM1 and an A
subunit with direct toxic activity. The binding of B subunit
to membrane GM1 may induce a conformational change in the toxin,
resulting in the entry of the A subunit into the cell. The B
subunit contains 103 amino acid residues, and Arg-35 and Trp-88
participate in binding to GM1. The mechanism of binding the heat-labile
toxin produced by enterotoxic Escherichia coli, which is structurally
related to cholera toxin is similar to the mechanism of cholera
toxin binding. Other ganglioside-binding bacterial toxins include
Tetanus toxin (GD1b), botulinum toxins (GT1b and GQ1b) and delta
toxin produced by Clostridium perfringens (GM2). Shiga toxin
produced by Shigella dysenteriae and Vero toxin produced by enterohaemorrhagic
E. coli bind to neutral glycosphingolipids having an alpha-1,4
galabiose moiety in the sugar chain, such as galabioside (Ga2Cer)
and ceramide trihexoside (Gb3Cer).
While many pathogenic bacteria also bind to glycosphingolipids
of host cell surface for colonization and infection, uropathogenic
E. coli which cause urinary tract infections can bind to glycosphingolipids
having an alpha-1,4 galabiose moiety at the non-reducing end
of the sugar chain (Gb3Cer, etc). There is evidence that bacteria
bind to glycosphingolipid receptor by recognizing not only the
terminal sequence but also the internal sequence of the sugar
chain. Uropathogenic E. coli can also bind to globoside (Gb4Cer)
and Forssman glycolipid, both of which have an alpha-1,4 galabiose
moiety internally in a sugar chain. Such receptor substances
are designated as isoreceptors. E. coli binds to glycosphingolipids
by pili which exist on the bacterial cell surface and are similar
to fibers or hairs. On the top of pili, there is an adhesin characterized
as a lectin. Several types of adhesin, with respect to their
sugar specificity, have been identified. They are the type I
adhesin of E. coli that are mannose specific, type P adhesin,
also of E. coli, specific for alpha-1,4 galabiose moiety, and
type S adhesin of E. coli, specific for sialylgalactose moiety.
It was reported that the amino acid sequence of P-adhesin is
similar as that of Shiga toxin because both recognize alpha-1,4
galabiose moiety of glycosphingolipid. Propionibacterium, which
causes skin disease, recognizes the lactosyl moiety of glycosphingolipids
as a binding epitope. These bacteria can bind strongly to lactosylceramide
and also bind to isoreceptors such as asialo GM1 (GA1) and asialo
GM2 (GA2). Because almost all glycosphingolipids contain a common
lactosyl moiety, Propionibacterium may be assumed to bind almost
all glycosphingolipids. However, the bacteria cannot bind to
any glycosphingolipids composed of a dihydroxy base and nonhydroxy
fatty acid in ceramide, even though these contain a lactosyl
moiety. This fact indicates that the binding epitope of the bacteria
also depends on the ceramide structure in addition to the lactosyl
moiety in sugar chain. Neisseria gonorrhoeae, which cause gonorrhoea,
also bind glycosphingolipids having a lactosyl moiety.
Conformational analysis of glycosphingolipids with terminal and
internal alpha-1,4 galabiose moiety showed that conformation
at this disaccharide is almost identical for all glycosphingolipids
with a bend in the sugar chain. The convex side of the bend probably
carries the binding epitope for many batceria.
Recently, it was found that Lactobacillus, a representative of
useful bacteria found in the intestinal tract, specifically binds
to some glycosphingolipids. These bacteria can bind to neutral
glycosphingolipids but not to gangliosides. |
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| References |
(1) |
Karlsson, K-A : Animal glycosphingolipids as membrane attachment
sites for bacteria. Annu.Rev.Biochem. 58, 309-350, 1989 |
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(2) |
Bock,K, Breimer, ME, Brignole, A, Hansson, GC, Karlsson,
K-A, Larson, G, Leffler, H, Samuelsson, BE, Stromberg, N, Eden,
CS : Specificity of binding of a strain of uropathogenic Escherichia
coli to Gal alpha 1-4 Gal-containing glycosphingolipids. J.Biol.Chem.
260, 8545-8551, 1985 |
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(3) |
Holmgren, J : Actions of cholera toxin and the prevention
and treatment of cholera. Nature, 292, 413-417, 1981 |
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