A novel NOD1- and CagA-independent pathway of interleukin-8 induction mediated by the Helicobacter pylori type IV secretion system

Authors

  • Rebecca J. Gorrell,

    1. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia
    2. Department of Microbiology, Monash University, Clayton, Vic., Australia
    Search for more papers by this author
  • Jyeswei Guan,

    1. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia
    Search for more papers by this author
  • Yue Xin,

    1. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia
    Current affiliation:
    1. School of Environmental and Life Sciences, University of Newcastle, Callaghan, NSW, Australia
    Search for more papers by this author
  • Mona Anoushiravani Tafreshi,

    1. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia
    Search for more papers by this author
  • Melanie L. Hutton,

    1. Department of Microbiology, Monash University, Clayton, Vic., Australia
    2. Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Clayton, Vic., Australia
    Search for more papers by this author
  • Michael A. McGuckin,

    1. Mucosal Diseases Program, Mater Medical Research Institute, Mater Health Services, South Brisbane, Qld, Australia
    Search for more papers by this author
  • Richard L. Ferrero,

    1. Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Clayton, Vic., Australia
    Search for more papers by this author
  • Terry Kwok

    Corresponding author
    1. Department of Microbiology, Monash University, Clayton, Vic., Australia
    • Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic., Australia
    Search for more papers by this author

For correspondence. E-mail terry.kwok@monash.edu; Tel. (+61) 3 9902 9216; Fax (+61) 3 9902 9500.

Summary

The type IV secretion system (T4SS) of Helicobacter pylori triggers massive inflammatory responses during gastric infection by mechanisms that are poorly understood. Here we provide evidence for a novel pathway by which the T4SS structural component, CagL, induces secretion of interleukin-8 (IL-8) independently of CagA translocation and peptidoglycan-sensing nucleotide-binding oligomerization domain 1 (NOD1) signalling. Recombinant CagL was sufficient to trigger IL-8 secretion, requiring activation of α5β1 integrin and the arginine–glycine–aspartate (RGD) motif in CagL. Mutation of the encoded RGD motif to arginine-glycine-alanine (RGA) in the cagL gene of H. pylori abrogated its ability to induce IL-8. Comparison of IL-8 induction between H. pylori ΔvirD4 strains bearing wild-type or mutant cagL indicates that CagL-dependent IL-8 induction can occur independently of CagA translocation. In line with this notion, exogenous CagL complemented H. pylori ΔcagL mutant in activating NF-κB and inducing IL-8 without restoring CagA translocation. The CagA translocation-independent, CagL-dependent IL-8induction involved host signalling via integrin α5β1, Src kinase, the mitogen-activated protein kinase (MAPK) pathway and NF-κB but was independent of NOD1. Our findings reveal a novel pathway whereby CagL, via interaction with host integrins, can trigger pro-inflammatory responses independently of CagA translocation or NOD1 signalling.

Ancillary