Chemical validation of molecular mimicry: interaction of cholera toxin with Campylobacter lipooligosaccharides.
It is generally believed that molecular mimicry between bacterial lipooligosaccharide (LOS) and nerve glycolipids may play an important pathogenic role in immune-mediated peripheral neuropathy. One of the putative infectious agents is Campylobacter jejuni (C. jejuni). To elucidate the structural basis for the molecular mimicry, we investigated the structure of the lipooligosaccharide (LOS) fraction of C. jejuni, strain HS19, and found that it includes at least two components, characterized as fast-and slow-moving bands (LF and LS) by thin-layer chromatography as revealed by cholera toxin B subunit (Ctxb) overlay. Structural analysis of the oligosaccharide portion of LS established that it had the following structure: Gal-GalNAc-(NeuAc)Gal-Hep-(Glc;PO(3)H)Hep-Kdo. The GM1-like epitope was validated by a terminal tetrasaccharide unit within this structure. On the other hand, analysis of LF revealed an entirely different structure: 1, 4'-bisphosphoryl glucosamine disaccharide N, N'-acylated by 3-(2-hydroxytetracosanoyloxy)octadecanoic acid at 2- and 2'-positions, which is consistent with that of lipid A. No GM1-like epitope was observed in LF. Both LS and LF interacted with Ctxb as demonstrated by TLC-overlay and sucrose density gradient centrifugation. Surprisingly, LF does not have the basic GM1 structure for interacting with Ctxb. Instead, the affinity of LF to Ctxb required that one or both of the phosphate groups be present in the glucosamine disaccharide residue because after alkaline phosphatase treatment the dephosphorylated LF was unable to bind to Ctxb. We conclude that LS is likely the component contributing to GM1-mimicry in autoimmune peripheral neuropathy and that the role of LF is not clear but may be associated with the initial activation of autoreactive T cells.
Usuki
Seigo
S
Institute of Molecular Medicine and Genetics and Institute of Neuroscience, Medical College of Georgia, Augusta, GA, 30912-2697, USA.
Pajaniappan
Mohanasundari
M
Thompson
Stuart A
SA
Yu
Robert K
RK
D016123:Campylobacter jejuni / Q000472:pathogenicity*; D002240:Carbohydrate Sequence; D002772:Cholera Toxin / Q000737:chemistry / Q000633:toxicity*; D002851:Chromatography, High Pressure Liquid; D008070:Lipopolysaccharides / Q000737:chemistry / Q000633:toxicity*; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D015394:Molecular Structure; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D008070:Lipopolysaccharides; C023023:lipid-linked oligosaccharides; D002772:Cholera Toxin