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

Cell Microbiol. 2013 Apr;15(4):554-70. doi: 10.1111/cmi.12055. Epub 2012 Nov 21.


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 α5 β1 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-8 induction involved host signalling via integrin α5 β1 , 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Bacterial / metabolism*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / immunology*
  • Bacterial Proteins / metabolism*
  • Bacterial Secretion Systems*
  • Cell Line
  • Helicobacter pylori / immunology*
  • Host-Pathogen Interactions
  • Humans
  • Integrin alpha5beta1 / metabolism
  • Interleukin-8 / metabolism*
  • Mutant Proteins / genetics
  • Mutant Proteins / immunology
  • Mutant Proteins / metabolism
  • Mutation
  • NF-kappa B / metabolism
  • Nod1 Signaling Adaptor Protein / metabolism*
  • Signal Transduction


  • Antigens, Bacterial
  • Bacterial Proteins
  • Bacterial Secretion Systems
  • Integrin alpha5beta1
  • Interleukin-8
  • Mutant Proteins
  • NF-kappa B
  • NOD1 protein, human
  • Nod1 Signaling Adaptor Protein
  • cagA protein, Helicobacter pylori
  • cagL protein, Helicobacter pylori