GPR17 as a Macrophage Sensor for Gram-Positive Peptidoglycan: Implications for Invasive Bacterial Infection

Invasive gram-positive infections, including necrotizing fasciitis, streptococcal toxic shock syndrome, and staphylococcal sepsis, disproportionately strike otherwise healthy individuals, implying a dominant role for host genetic susceptibility in innate bacterial surveillance. Here we present transcriptomic, structural pharmacophore, and molecular docking evidence supporting GPR17, a G protein-coupled receptor phylogenetically intermediate between purinergic P2Y receptors and cysteinyl leukotriene receptors, as a candidate surface-expressed pattern recognition receptor for gram-positive peptidoglycan on tissue macrophages. Reanalysis of Human Protein Atlas single-cell RNA-seq data reveals that GPR17 is expressed predominantly on tissue macrophages (31.7 nTPM) and monocytes (12 to 18 nTPM), with markedly lower expression in lymphoid lineages (<2 nTPM). AutoDock Vina docking of 15 compounds against the AlphaFold-predicted GPR17 structure identifies UDP-muramic acid (UDP-Mur), a peptidoglycan biosynthetic intermediate, as a high-affinity ligand for the GPR17 orthosteric pocket (−7.2 kcal/mol), within 0.2 kcal/mol of UDP-glucose and UDP-galactose (−7.4 kcal/mol each). N-acetylated peptidoglycan intermediates (UDP-MurNAc, UDP-GlcNAc) dock poorly (−4.3 and −4.4 kcal/mol), suggesting a steric constraint at the C2 position of the hexose ring. Critically, UDP-glucose has never been independently confirmed as a GPR17 agonist despite multiple attempts across at least eight functional assay platforms. We propose that UDP-glucose and UDP-galactose function as endogenous neutral antagonists that occupy the GPR17 orthosteric pocket without activating downstream signaling, while UDP-Mur may be the true agonist whose C3 lactyl ether likely provides the pharmacophoric contact necessary for receptor activation. This framework may resolve the longstanding GPR17 deorphanization controversy, establish a mechanistic basis for peptidoglycan surveillance through a mammalian GPCR, and provide a molecular explanation for the clinical association between NSAID use and adverse outcomes in invasive gram-positive infections, including necrotizing fasciitis.