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A novel link between Campylobacter jejuni bacteriophage defence, virulence and Guillain–Barré syndrome

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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.

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Acknowledgements

This work was supported by a grant from the Human Frontier Science Program (RGP 38/2003) and by the BBSRC Institute Strategic Programme Grant to the IFR. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. We would like to thank Theo Hoogenboezem (Erasmus MC) for the mass spectrometry analysis of the recombinant Csn1 protein for polyclonal antibody production and Ian Connerton for bacteriophage CP28.

Conflicts of interest

Alex van Belkum is an employee of bioMérieux. There are no conflicts of interest to disclose.

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Authors and Affiliations

  1. Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center Rotterdam, ‘s-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands

    R. Louwen, D. Horst-Kreft, G. de Knegt, M. Hamersma, A. P. Heikema, H. P. Endtz & A. van Belkum

  2. Central Veterinary Institute (CVI), Wageningen UR, Lelystad, The Netherlands

    A. G. de Boer & P. T. J. Willemsen

  3. Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, University Utrecht, Utrecht, The Netherlands

    L. van der Graaf & J. A. Wagenaar

  4. Division of Food Sciences, University of Nottingham, Nottingham, UK

    A. R. Timms

  5. Departments of Neurology and Immunology, Erasmus MC, Rotterdam, The Netherlands

    B. C. Jacobs

  6. Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands

    J. van der Oost

  7. Host–Microbe Interactomics, Animal Sciences, Wageningen University, Wageningen, The Netherlands

    J. M. Wells

  8. Department of Pediatric Gastroenterology, Wilhelmina Children’s Hospital, University Medical Center, Utrecht, The Netherlands

    E. E. S. Nieuwenhuis & P. van Baarlen

  9. Institute of Food Research, Norwich, UK

    A. H. M. van Vliet

  10. Microbiology Unit, bioMérieux, La Balme les Grottes, France

    A. van Belkum

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  1. R. Louwen
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Correspondence to R. Louwen.

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Louwen, R., Horst-Kreft, D., de Boer, A.G. et al. A novel link between Campylobacter jejuni bacteriophage defence, virulence and Guillain–Barré syndrome. Eur J Clin Microbiol Infect Dis 32, 207–226 (2013). https://doi.org/10.1007/s10096-012-1733-4

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