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.

Although the role of Toll-like receptors in extracellular bacterial sensing has been investigated intensively, intracellular detection of bacteria through Nod molecules remains largely uncharacterized. Here, we show that human Nod1 specifically detects a unique diaminopimelate-containing N-acetylglucosamine-N-acetylmuramic acid (GlcNAc-MurNAc) tripeptide motif found in Gram-negative bacterial peptidoglycan, resulting in activation of the transcription factor NF-kappaB pathway. Moreover, we show that in epithelial cells (which represent the first line of defense against invasive pathogens), Nod1is indispensable for intracellular Gram-negative bacterial sensing.

Transient receptor potential (TRP) proteins are cation-selective channels that function in processes as diverse as sensation and vasoregulation. Mammalian TRP channels that are gated by heat and capsaicin (>43 degrees C; TRPV1 (ref. 1)), noxious heat (>52 degrees C; TRPV2 (ref. 2)), and cooling (< 22 degrees C; TRPM8 (refs 3, 4)) have been cloned; however, little is known about the molecular determinants of temperature sensing in the range between approximately 22 degrees C and 40 degrees C. Here we have identified a member of the vanilloid channel family, human TRPV3 (hTRPV3) that is expressed in skin, tongue, dorsal root ganglion, trigeminal ganglion, spinal cord and brain. Increasing temperature from 22 degrees C to 40 degrees C in mammalian cells transfected with hTRPV3 elevated intracellular calcium by activating a nonselective cationic conductance. As in published recordings from sensory neurons, the current was steeply dependent on temperature, sensitized with repeated heating, and displayed a marked hysteresis on heating and cooling. On the basis of these properties, we propose that hTRPV3 is thermosensitive in the physiological range of temperatures between TRPM8 and TRPV1.