We aim to identify determinants of inflammatory pathogenesis to guide the development of novel therapeutics to treat pertussis. Single cell and bulk transcriptomic studies identified NOD-like receptor signaling and peptidoglycan recognition proteins (PGLYRPs) as key elements of the hyper-inflammatory response observed in the lungs of B. pertussis infected mice. During peptidoglycan (PGN) recycling, B. pertussis releases a monomeric fragment of PGN called tracheal cytotoxin (TCT), an energy-costly and immune alarming decision. TCT contributes to tracheal cell extrusion and prevention of mucocillary clearance of pertussis, but little is known on TCT’s role in triggering immune responses. We hypothesized that TCT is a critical mediator of the host inflammatory response. To investigate the pathogenesis and immunology of TCT responses, we used a combination of over- and under- TCT releasing mutant strains, reporter assays and knockout mice. Interestingly PGN in the sacculus signals via NOD2 but TCT drives a NOD1 response. The ability of TCT to signal via NOD1 was enhanced by PGLYRP1, revealing a novel role for PGLYRPs in PGN-mediated signaling. We infected wild- type mice with TCT over- and under-producing strains, compared lung pathology and discovered that TCT promoted a less inflammatory NOD1-mediated response, diverting from a more potent NOD2 response, suggesting NOD1/2 play opposing roles in exacerbating lung pathology. These data suggest that TCT polarizes NOD responses towards a less inflammatory NOD1-response. To confirm this, we are actively performing studies in NOD1/2 knockout mice. These findings have exciting implications for pertussis vaccine development, PGN-mediated inflammatory disorders, and development of host-directed therapeutics.