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.
