Murine Nod1 but not its human orthologue mediates innate immune detection of tracheal cytotoxin.
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.
Magalhaes
Joao Gamelas
JG
Unité de Pathogénie Microbienne Moléculaire INSERM U389, Paris, France.
Philpott
Dana J
DJ
Nahori
Marie-Anne
MA
Jéhanno
Muguette
M
Fritz
Joerg
J
Le Bourhis
Lionel
L
Viala
Jérôme
J
Hugot
Jean-Pierre
JP
Giovannini
Marco
M
Bertin
John
J
Lepoivre
Michel
M
Mengin-Lecreulx
Dominique
D
Sansonetti
Philippe J
PJ
Girardin
Stephen E
SE
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D003603:Cytotoxins / Q000008:administration & dosage / Q000494:pharmacology*; D017930:Genes, Reporter; D006801:Humans; D007113:Immunity, Innate; D007274:Injections, Intraperitoneal; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008156:Luciferases / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053474:Nod1 Signaling Adaptor Protein; D055457:Nodal Protein; D010457:Peptidoglycan / Q000737:chemistry / Q000494:pharmacology; D013045:Species Specificity; D014132:Trachea / Q000166:cytology / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D003603:Cytotoxins; C119067:NOD1 protein, human; C526007:NODAL protein, human; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D055457:Nodal Protein; C526008:Nodal protein, mouse; D010457:Peptidoglycan; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D008156:Luciferases