Oral Presentation HUPO 2019 - 18th Human Proteome Organization World Congress

Systematic chemical synthesis and immunological function of Campylobacter jejuni lipid As (#107)

Atsushi Shimoyama 1 , Sho Nakagawa 1 , Yoshifumi Matsuura 1 , Koichi Fukase 1
  1. Osaka University, Toyonaka, OSAKA, Japan

A Gram-negative bacteria Campylobacter jejuni produces lipooligosaccharide (LOS) as an outer membrane component. C. jejuni LOS is composed of core oligosaccharide part and glycolipid part termed “lipid A”. Since C. jejuni oligosaccharides have molecular homology with gangliosides in human nervous tissues, C. jejuni infection facilitates the induction of auto-antibodies to gangliosides, leading autoimmune diseases1). Although immunostimulation by lipid A proved to be critical to promote antibody production, the role of the C. jejuni lipid A in auto-antibody production has not been elucidated because of the synthetic difficulty in C. jejuni lipid A.

General lipid As are composed of only glucosamine (GlcN). C. jejuni lipid A, however, has structural diversity in the sugar framework consisting in GlcN and 2,3-diaminoglucose (GlcN3N)2). We thus established a diversity oriented synthetic strategy via the key disaccharide intermediates having GlcN-GlcN, GlcN-GlcN3N, GlcN3N-GlcN and GlcN3N-GlcN3N framework respectively, and accomplished the first chemical synthesis of four types C. jejuni lipid As.

We then measured the NF-κB activation of C. jejuni lipid As in HEK-Blue™ TLR4 cells and found that the slight difference in the sugar frameworks greatly affects the immunological activity of lipid A and GlcN-GlcN3N framework is most important in immunoactivation. The GlcN-GlcN type and GlcN-GlcN3N type lipid As showed agonistic activity (GlcN-GlcN3N type was stronger than GlcN-GlcN type), whereas GlcN3N-GlcN type and GlcN3N-GlcN3N type showed no activity.

On the other hand, Helicobacter pylori having the same molecular homology as C. jejuni does not induce immunological cross-reaction3). We have synthesized H. pylori lipid A and found that it acts as an antagonist against TLR4-MD2 while inducing chronic inflammatory signals4). These results suggest that the immunological cross-reaction is regulated by the differences in lipid A function.

  1. N. Yuki, Lancet Infectious Diseases, 2001, 1, 29.
  2. A. P. Moran et al., Eur. J. Biochem., 1991, 198, 459.
  3. D. A. Sack et al., J. Clin. Microbiol., 1998, 36, 2043.
  4. A. Shimoyama et al., Chem Eur J, 2011, 17, 14464.