title: A novel link between Campylobacter jejuni bacteriophage defence, virulence and Guillain-Barré syndrome.
abstract: Guillain-Barré syndrome (GBS) is a post-infectious disease in which the human peripheral nervous system is affected after infection by specific pathogenic bacteria, including Campylobacter jejuni. GBS is suggested to be provoked by molecular mimicry between sialylated lipooligosaccharide (LOS) structures on the cell envelope of these bacteria and ganglioside epitopes on the human peripheral nerves, resulting in autoimmune-driven nerve destruction. Earlier, the C. jejuni sialyltransferase (Cst-II) was found to be linked to GBS and demonstrated to be involved in the biosynthesis of the ganglioside-like LOS structures. Apart from a role in pathogenicity, we report here that Cst-II-generated ganglioside-like LOS structures confer efficient bacteriophage resistance in C. jejuni. By bioinformatic analysis, it is revealed that the presence of sialyltransferases in C. jejuni and other potential GBS-related pathogens correlated significantly with the apparent degeneration of an alternative anti-virus system: type II Clusters of Regularly Interspaced Short Palindromic Repeat and associated genes (CRISPR-Cas). Molecular analysis of the C. jejuni CRISPR-Cas system confirmed the bioinformatic investigation. CRISPR degeneration and mutations in the cas genes cas2, cas1 and csn1 were found to correlate with Cst-II sialyltransferase presence (p < 0.0001). Remarkably, type II CRISPR-Cas systems are mainly found in mammalian pathogens. To study the potential involvement of this system in pathogenicity, we inactivated the type II CRISPR-Cas marker gene csn1, which effectively reduced virulence in primarily cst-II-positive C. jejuni isolates. Our findings indicate a novel link between viral defence, virulence and GBS in a pathogenic bacterium.
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, 's-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands. r.louwen@erasmusmc.nl
authors.forename: R
authors.initials: R
authors.lastname: Louwen
authors.forename: D
authors.initials: D
authors.lastname: Horst-Kreft
authors.forename: A G
authors.initials: AG
authors.lastname: de Boer
authors.forename: L
authors.initials: L
authors.lastname: van der Graaf
authors.forename: G
authors.initials: G
authors.lastname: de Knegt
authors.forename: M
authors.initials: M
authors.lastname: Hamersma
authors.forename: A P
authors.initials: AP
authors.lastname: Heikema
authors.forename: A R
authors.initials: AR
authors.lastname: Timms
authors.forename: B C
authors.initials: BC
authors.lastname: Jacobs
authors.forename: J A
authors.initials: JA
authors.lastname: Wagenaar
authors.forename: H P
authors.initials: HP
authors.lastname: Endtz
authors.forename: J
authors.initials: J
authors.lastname: van der Oost
authors.forename: J M
authors.initials: JM
authors.lastname: Wells
authors.forename: E E S
authors.initials: EE
authors.lastname: Nieuwenhuis
authors.forename: A H M
authors.initials: AH
authors.lastname: van Vliet
authors.forename: P T J
authors.initials: PT
authors.lastname: Willemsen
authors.forename: P
authors.initials: P
authors.lastname: van Baarlen
authors.forename: A
authors.initials: A
authors.lastname: van Belkum
mesh_terms: D001435:Bacteriophages / Q000254:growth & development*; D002169:Campylobacter Infections / Q000150:complications* / Q000276:immunology / Q000382:microbiology; D016123:Campylobacter jejuni / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity* / Q000821:virology; D019295:Computational Biology; D004269:DNA, Bacterial / Q000235:genetics; D005732:Gangliosides / Q000276:immunology / Q000378:metabolism*; D020275:Guillain-Barre Syndrome / Q000382:microbiology*; D006801:Humans; D037521:Virulence Factors / Q000276:immunology / Q000378:metabolism*
chemical_list: D004269:DNA, Bacterial; D005732:Gangliosides; D037521:Virulence Factors