cholesteryl-glucoside and Lyme-Disease

Steryl glycosides, sterols glycosylated at the 3β-hydroxy group, have been widely found in plants, algae, and fungi, but are rare in bacteria and animals. Glycosylation of sterols is known to modify properties of the cell membrane and confer resistance against stresses by freezing or heat-shock on cells. Furthermore, accumulating evidence obtained from recent research suggests important biological functions of steryl glycosides, including regulation of host defenses against pathogens, lipid metabolism, and developmental events. This review is focused on the immunological functions of steryl glycosides, such as modulation of host immune functions upon exposure to cholesteryl glycosides produced by pathogenic bacteria.

Topics: Animals; Borrelia burgdorferi; Borrelia Infections; Cholesterol; Galactosides; Glycosides; Glycosylation; Helicobacter pylori; Humans; Immune System; Immunogenetics; Killer Cells, Natural; Lipids; Lyme Disease; Mice; Mice, Inbred C57BL; Models, Biological; Models, Chemical; Sterols

Lyme disease (LD) is the most common tick-borne disease in Europe, North America, and Asia. The etiologic agents of LD are spirochetes of the group Borrelia burgdorferi sensu lato, which possess a lipid content of 25-30% of the dry weight. The major glycolipid cholesteryl 6-O-acyl-beta-D-galactopyranoside (ACGal), present in B. burgdorferi sensu stricto, B. afzelii, and B. garinii, is a specific and highly prevalent antigen frequently recognized by antibodies in late-stage LD. Here we report a convenient route for the chemical synthesis of ACGal by employing a combination of chemical synthesis steps with enzymatic transformations. This synthesized molecule was compared with bacterial extracts by immunoblots with patient sera, confirming the preserved antigenicity. Next, a glycolipid library derived from the native molecules with variations in the fatty acyl moiety and derivatives in which the cholesterol has been replaced was designed and synthesized. The chemical structures were confirmed by 1D and 2D NMR spectroscopy and mass spectrometry. The native and synthetic glycolipids were utilized in immunoblots to determine the epitope recognized by antibodies in patient sera. By this method we could demonstrate that galactose, cholesterol, and a fatty acid with a minimal chain length of four carbon atoms comprises the essential structure for recognition by antibodies. Finally, this finding allowed the synthesis of a functionalized ACGal with an omega-mercapto group at the fatty acid and a facile protection and deprotection strategy. This antigenic hapten can be conjugated to a carrier protein to effect immunization against Lyme disease.

Topics: Antibodies, Bacterial; Antigens, Bacterial; Borrelia burgdorferi; Cholesterol; Epitopes; Glycolipids; Humans; Lyme Disease; Lyme Disease Vaccines; Stereoisomerism