Insights from the redefinition of Helicobacter pylori lipopolysaccharide O-antigen and core-oligosaccharide domains

Abstract

H. pylori is a Gram-negative extracellular bacterium, first discovered by the Australian physicians Barry Marshall and Robin Warren in 1982, that colonises the human stomach mucosa. It is the leading cause of peptic ulcer and commonly infects humans worldwide with prevalence as high as 90% in some countries. H. pylori infection usually results in asymptomatic chronic gastritis, however 10-15% of cases develop duodenal or gastric ulcers and 1-3% develop stomach cancer. Infection is generally acquired during childhood and persists for life in the absence of antibiotic treatment. H. pylori has had a long period of co-evolution with humans, going back to human migration out of Africa. This prolonged relationship is likely to have shaped the overall host-pathogen interactions and repertoire of virulence strategies which H. pylori employs to establish robust colonisation, escape immune responses and persist in the gastric niche. In this regard, H. pylori lipopolysaccharide (LPS) is a key surface determinant in establishing colonisation and persistence via host mimicry and resistance to cationic antimicrobial peptides. Thus, elucidation of the H. pylori LPS structure and corresponding biosynthetic pathway represents an important step towards better understanding of H. pylori pathogenesis and the development of novel therapeutic interventions.

Keywords: Helicobacter pylori; antibiotic adjuvant; lipopolysaccharide structure; persistence; therapy.

Figure 1. Figure 1: Previously proposed and the redefined structures of H. pylori LPS from strain 26695.

A) Previously in H. pylori strain 26695, the LPS O-antigen domain was proposed to contain the Lewis antigen only, the LPS core-oligosaccharide domain was divided into an inner core and outer core. The inner core is a hexa-saccharide comprised of Glc-Gal-DD-Hep-LD-Hep-LD-Hep-KDO, the outer core is comprised of the Trio, the heptan and glucan. B) Based on our recent study, the LPS structure in H. pylori strain 26695 is redefined: the O-antigen encompasses more than the Lewis antigen, but also the previously defined outer core structure (the Trio, the glucan and the heptan), whereas the core-oligosaccharide only contains the short hexa-saccharide which was previously assigned as the inner core. Figure reproduced from Li et al. 2017 (doi: 10.1371/journal.ppat.1006280) under the Creative Commons CC BY 4.0 license.

Figure 2. Figure 2: Inhibitor targeting the H. pylori LPS biosynthesis pathway.

LPS structure up to the Trio is conserved among H. pylori strains and required for colonisation. Thus, corresponding LPS biosynthetic enzymes involved in the assembly of the LPS conserved domains, such as HP1284, represent attractive virulence targets for the design of novel therapeutic agents for managing persistent H. pylori infection. Figure reproduced from Li et al. 2017 (doi: 10.1371/journal.ppat.1006280) under the Creative Commons CC BY 4.0 license.