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Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island

Nature Immunology volume 5, pages 1166–1174 (2004)Cite this article

Abstract

Epithelial cells can respond to conserved bacterial products that are internalized after either bacterial invasion or liposome treatment of cells. We report here that the noninvasive Gram-negative pathogen Helicobacter pylori was recognized by epithelial cells via Nod1, an intracellular pathogen-recognition molecule with specificity for Gram-negative peptidoglycan. Nod1 detection of H. pylori depended on the delivery of peptidoglycan to host cells by a bacterial type IV secretion system, encoded by the H. pylori cag pathogenicity island. Consistent with involvement of Nod1 in host defense, Nod1-deficient mice were more susceptible to infection by cag pathogenicity island–positive H. pylori than were wild-type mice. We propose that sensing of H. pylori by Nod1 represents a model for host recognition of noninvasive pathogens.

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Figure 1: HEK293 cells express Nod1 mRNA.
Figure 2: Nod1 mediates epithelial cell responses to cagPAI-positive H. pylori bacteria.
Figure 3: H. pylori peptidoglycan induces proinflammatory responses in epithelial cells.
Figure 4: A functional cagPAI is required for H. pylori delivery of peptidoglyc an to epithelial cells.
Figure 5: Dual immunohistochemical and silver labeling of H. pylori cocultured AGS cells.
Figure 6: H. pylori–induced NF-κB activation in HEK293 cells does not depend on bacterial internalization.
Figure 7: Nod1-deficient mice have a heightened susceptibility to cagPAI-positive H. pylori bacteria.
Figure 8: Primary gastric epithelial cells from Nod1-deficient mice produce lower amounts of MIP-2 in response to stimulation by H. pylori bacteria.

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Acknowledgements

We thank D. Blanot for the LysA assays; S. Saurin and M. Tanguy for histological analyses; R. Peek for the H. pylori B128 strain; L. Bougneres for advice regarding tyrosine phosphorylation assays; members of Programme Transversal de Recherche (PTR) project 94 for sharing information and materials; and L. Ferrero for reading of the manuscript. J.B., D.J.P. and R.L.F. share senior authorship. Supported by the Institut Pasteur (PTR94; S.E.G., D.J.P. and R.L.F.); Health Research Board of Ireland (A.P.M.); Laboratoires Sanofi-Synthélabo, La Société des Eaux Minérales d'Evian and INSERM (J.V.); the French Ministry of Science (C.C.); the Fundação para a Ciência e a Tecnologia of Portugal (I.G.B.); and Danone Vitapole (S.E.G.). P.J.S. is a Howard Hughes International Research Scholar.

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Author notes

  1. Richard L Ferrero

    Present address: Department of Microbiology, Monash University, Clayton, 3800, Victoria, Australia

Authors and Affiliations

  1. Groupe d'Immunité Innée et Signalisation, Institut National de la Santé et de la Recherche Médicale U389, Institut Pasteur, Paris, France

    Jérôme Viala, Rafika Athman & Dana J Philpott

  2. Unité de Pathogénie Bactérienne des Muqueuses, Institut National de la Santé et de la Recherche Médicale U389, Institut Pasteur, Paris, France

    Catherine Chaput, Ivo G Boneca, Agnès Labigne & Richard L Ferrero

  3. Unité de Recherche et d'Expertise Histotechnologie et Pathologie, Institut National de la Santé et de la Recherche Médicale U389, Institut Pasteur, Paris, France

    Ana Cardona & Michel R Huerre

  4. Unité de Pathogénie Microbienne Moléculaire, Institut National de la Santé et de la Recherche Médicale U389, Institut Pasteur, Paris, France

    Stephen E Girardin & Philippe J Sansonetti

  5. Department of Microbiology, National University of Ireland, Galway, Ireland

    Anthony P Moran

  6. Unité de Biologie Moléculaire de l'Expression Génique, Institut Pasteur, Paris, France

    Sylvie Mémet & Dana J Philpott

  7. Millenium Pharmaceuticals, Cambridge, Massachusetts, USA

    Anthony J Coyle, Peter S DiStefano & John Bertin

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Supplementary information

Supplementary Fig. 1

Absence of cagA and cagF. gene homologues in H. felis by Southern hybridization. (PDF 61 kb)

Supplementary Fig. 2

A mutation in the slt gene does not affect the H. pylori type IV secretion apparatus. (PDF 94 kb)

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Viala, J., Chaput, C., Boneca, I. et al. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol 5, 1166–1174 (2004). https://doi.org/10.1038/ni1131

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