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EMBO reports 6, 12, 1201–1207 (2005)
doi:10.1038/sj.embor.7400552
Published online: 7 October 2005
Murine Nod1 but not its human orthologue mediates innate immune detection of tracheal cytotoxin
Joao Gamelas Magalhaes1, 10, Dana J Philpott2, 10, Marie-Anne Nahori3, Muguette Jéhanno2, Joerg Fritz2, Lionel Le Bourhis2, Jérôme Viala2, Jean-Pierre Hugot4, Marco Giovannini5, John Bertin6, Michel Lepoivre7, Dominique Mengin-Lecreulx8, Philippe J Sansonetti1 & Stephen E Girardin1, 9
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1 Unité de Pathogénie Microbienne Moléculaire INSERM U389
2 Groupe Immunité Innée et Signalisation
3 Unité des Interactions Bactéries-Cellules, Institut Pasteur, 28, Rue du Dr. Roux, 75724 Paris Cedex 15, France
4 Groupe Inserm Avenir, Hôpital Robert Debré, 48, Bd Serurier, 75019 Paris, France
5 Génomique fonctionnelle des tumeurs solides, Inserm U674, Paris, France
6 Synta Pharmaceuticals Corp., 45 Hartwell Ave, Lexington, Massachusetts 0242, USA
7 Oxydes d'azote, Inflammation et Immunité
8 Enveloppes Bactériennes et Antibiotiques, IBBMC, UMR 8619 CNRS, Université Paris-Sud, Bât. 430, 91405 Orsay, France
9 Groupe Inserm Avenir Peptidoglycan and Innate Immunity, Institut Pasteur, 28, Rue du Dr. Roux, 75724 Paris Cedex 15, France
10 These authors contributed equally to this work
To whom correspondence should be addressed
Dana J Philpott Tel: +33 1 45 68 85 93; E-mail: philpott@pasteur.fr
Stephen E Girardin Tel: +33 1 40 61 37 71; E-mail: girardin@pasteur.fr
Received 14 June 2005; Accepted 9 September 2005; Published online 7 October 2005.
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Abstract
Tracheal cytotoxin (TCT) was originally described as the minimal effector that was able to reproduce the cytotoxic response of Bordetella pertussis on ciliated epithelial cells. This molecule triggers pleiotropic effects such as immune stimulation or slow-wave sleep modulation. Further characterization identified TCT as a specific diaminopimelic acid (DAP)-containing muropeptide, GlcNAc-(anhydro)MurNAc-L-Ala-D-Glu-mesoDAP-D-Ala. Here, we show that the biological activity of TCT depends on Nod1, an intracellular sensor of bacterial peptidoglycan. However, Nod1-dependent detection of TCT was found to be host specific, as human Nod1 (hNod1) poorly detected TCT, whereas mouse Nod1 (mNod1) did so efficiently. More generally, hNod1 required a tripeptide (L-Ala-D-Glu-mesoDAP) for efficient sensing of peptidoglycan, whereas mNod1 detected a tetrapeptide structure (L-Ala-D-Glu-mesoDAP-D-Ala). In murine macrophages, TCT stimulated cytokine secretion and NO production through Nod1. Finally, in vivo, injection of the tetrapeptide structure in mice triggered a transient yet strong release of cytokines into the bloodstream and the maturation of macrophages, in a Nod1-dependent manner. This study thereby identifies Nod1 as the long sought after sensor of TCT in mammals.
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