Biomolecule sulphation and novel methylations related to Guillain-Barre syndrome-associated Campylobacter jejuni serotype HS:19

Authors: HEIKEMA, ASTRID - ERASMUS MEDICAL CENTER; STREPIS, NIKOLAOS - ERASMUS MEDICAL CENTER; HORST-KREFT, DEBORAH - ERASMUS MEDICAL CENTER; Huynh, Steven; ZOMER, ALDERT - UTRECHT UNIVERSITY; KELLY, DAVID - UNIVERSITY OF SHEFFIELD; COOPER, KERRY - UNIVERSITY OF ARIZONA; Parker, Craig

Submitted to: Microbial Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/28/2021
Publication Date: 11/1/2021
Citation: Heikema, A.P., Strepis, N., Horst-Kreft, D., Huynh, S., Zomer, A., Kelly, D.J., Cooper, K.K., Parker, C.T. 2021. Biomolecule sulphation and novel methylations related to Guillain-Barre syndrome-associated Campylobacter jejuni serotype HS:19. Microbial Genomics. 7(11). Article 000660. https://doi.org/10.1099/mgen.0.000660.
DOI: https://doi.org/10.1099/mgen.0.000660

Interpretive Summary: Campylobacter jejuni, a foodborne pathogen, is a worldwide leading cause of bacterial gastroenteritis. Besides diarrheal disease, an infection with C. jejuni can also result in the immune-mediated neuropathy Guillain-Barre syndrome (GBS). Strains of C. jejuni that produce sialylated lipooligosaccharides (LOS) can cause the immune-mediated disease Guillain-Barré syndrome (GBS) where cross-reactive antibodies to sialylated LOS bind to similar ganglioside structures and trigger complement-mediated immune activation. The risk of GBS after infection with C. jejuni Penner serotype HS:19 is estimated to be at least six times higher than the average risk. Aside from LOS biosynthesis genes, genomic characteristics that promote an increased risk for GBS, following C. jejuni HS:19 infection, remain uncharacterised. We performed genome sequencing, alignments and single nucleotide polymorphisms analysis on a subset, and pan-genome analysis on a large number of genomes to compare HS:19 with non-HS:19 C. jejuni genome sequences. Comparison of 36 C. jejuni HS:19 with 874 C. jejuni non-HS:19 genome sequences led to the identification of three single genes and ten clusters containing contiguous genes that were significantly associated with C. jejuni HS:19. One gene cluster of seven genes, localized downstream of the capsular biosynthesis locus, was related to sulfation of biomolecules. This cluster also encoded the campylobacter sialyl transferase Cst-I. Interestingly, sulfated bacterial biomolecules such as polysaccharides can promote immune responses and, therefore, (in the presence of sialic acid) may play a role in the development of GBS. Additional gene clusters included those involved in persistence-mediated pathogenicity and gene clusters involved in restriction-modification systems. Furthermore, characterisation of methylomes of two HS:19 strains exhibited novel methylation patterns that could differentially effect gene expression patterns of C. jejuni HS:19 strains. Our study provides novel insight into possible virulence factors of C. jejuni associated with the HS:19 serotype that may explain the increased risk of GBS.

Technical Abstract: Campylobacter jejuni strains that produce sialylated lipooligosaccharides (LOS) can cause the immune-mediated disease Guillain-Barré syndrome (GBS). The risk of GBS after infection with C. jejuni Penner serotype HS:19 is estimated to be at least six times higher than the average risk. Aside from LOS biosynthesis genes, genomic characteristics that promote an increased risk for GBS, following C. jejuni HS:19 infection, remain uncharacterised. We performed genome sequencing, alignments and single nucleotide polymorphisms analysis on a subset, and pan-genome analysis on a large number of genomes to compare HS:19 with non-HS:19 C. jejuni genome sequences. Comparison of 36 C. jejuni HS:19 with 874 C. jejuni non-HS:19 genome sequences led to the identification of three single genes and ten clusters containing contiguous genes that were significantly associated with C. jejuni HS:19. One gene cluster of seven genes, localised downstream of the capsular biosynthesis locus, was related to sulphation of biomolecules. This cluster also encoded the campylobacter sialyl transferase Cst-I. Interestingly, sulphated bacterial biomolecules such as polysaccharides can promote immune responses and, therefore, (in the presence of sialic acid) may play a role in the development of GBS. Additional gene clusters included those involved in persistence-mediated pathogenicity and gene clusters involved in restriction-modification systems. Furthermore, characterisation of methylomes of two HS:19 strains exhibited novel methylation patterns (5'-CATG-3 and 5'-m6AGTNNNNNNRTTG-3) that could differentially effect gene expression patterns of C. jejuni HS:19 strains. Our study provides novel insight into possible virulence factors of C. jejuni associated with the HS:19 serotype that may explain the increased risk of GBS.