East-Asian Helicobacter pylori strains synthesize heptan-deficient lipopolysaccharide.

Hong Li,Mohammed Benghezal,Hong Tang,Stuart M Haslam,Tingting Liao,Keith A Stubbs,Barbara Mulloy,Renwei Hu,Xuenan Pi,Tiandi Yang,Binit Lamichhane,Anne Dell,Yan Xie,Ying Shi,Aleksandra W Debowski,Xiaoqiong Tang,Barry J Marshall,Tiankuo Yang,Michaël Marceau ,Chin Yen Tay ,Hans Olof Nilsson ,Yanjiao Shen ,Yong Hong Luo

doi:10.1371/journal.pgen.1008497

Abstract

The lipopolysaccharide O-antigen structure expressed by the European Helicobacter pylori model strain G27 encompasses a trisaccharide, an intervening glucan-heptan and distal Lewis antigens that promote immune escape. However, several gaps still remain in the corresponding biosynthetic pathway. Here, systematic mutagenesis of glycosyltransferase genes in G27 combined with lipopolysaccharide structural analysis, uncovered HP0102 as the trisaccharide fucosyltransferase, HP1283 as the heptan transferase, and HP1578 as the GlcNAc transferase that initiates the synthesis of Lewis antigens onto the heptan motif. Comparative genomic analysis of G27 lipopolysaccharide biosynthetic genes in strains of different ethnic origin revealed that East-Asian strains lack the HP1283/HP1578 genes but contain an additional copy of HP1105 and JHP0562. Further correlation of different lipopolysaccharide structures with corresponding gene contents led us to propose that the second copy of HP1105 and the JHP0562 may function as the GlcNAc and Gal transferase, respectively, to initiate synthesis of the Lewis antigen onto the Glc-Trio-Core in East-Asian strains lacking the HP1283/HP1578 genes. In view of the high gastric cancer rate in East Asia, the absence of the HP1283/HP1578 genes in East-Asian H. pylori strains warrants future studies addressing the role of the lipopolysaccharide heptan in pathogenesis.

Highlights

Helicobacter pylori is a human gastric pathogen that infects more than half of the world’s population [1]
Through systematic mutagenesis of glycosyltransferase genes in the model strain G27 combined with lipopolysaccharide structural analysis, we identified novel glycosyltransferases and established the first complete lipopolysaccharide biosynthetic pathway in G27
Future studies are needed to address whether the lack of heptan in lipopolysaccharide of East-Asian H. pylori strains is related to the high gastric cancer rate in East Asia, accounting for almost half of the worldwide gastric cancer cases

Summary

Introduction

Helicobacter pylori is a human gastric pathogen that infects more than half of the world’s population [1]. It causes active gastritis in all colonised subjects [2], and making it the most important aetiological factor for gastric cancer [2,3], the third leading cause of cancer related death worldwide [4]. The pathological outcomes of H. pylori chronic colonisation reflect the subtle host-pathogen interactions dictated by bacterial and host genetics and environmental factors. In this regard, H. pylori lipopolysaccharide (LPS), a major bacterial surface molecule, plays essential roles in host-pathogen interactions [6,7,8,9]. ADP-LD-Hep is the precursor of the LD-Hep units conservatively present in the LPS core-

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