A dual role for PGLYRP1 in host defense and immune regulation during B. pertussis infection

Bordetella pertussis , the etiologic agent of whooping cough, remains a serious public health concern despite widespread vaccination. Improved therapeutics and vaccines are urgently needed. Host recognition of bacterial peptidoglycan (PGN), including B. pertussis extracellular PGN fragment tracheal cytotoxin (TCT) shapes the immune response to infection. Peptidoglycan recognition proteins (PGLYRPs) are a conserved innate immune family that bind bacterial PGN and are primarily known for bactericidal activity in mammals; however, their immune modulatory roles are beginning to gain appreciation. The role of PGLYRPs in mammalian host defenses to Gram-negative pathogens, such as B. pertussis , remains largely unknown. Here, using knockout mice, single-cell and bulk transcriptomics, and functional assays, we identify a dual role for PGLYRP1 in modulating host immune responses to B. pertussis . PGLYRP1 contributes to antibacterial responses and paradoxically dampens inflammatory responses and inhibits bacterial killing later in infection. Mechanistically, PGLYRP1 enhances NOD1 signaling in response to TCT while suppressing NOD2− and triggering receptor expressed on myeloid cells-1 (TREM-1)-mediated inflammatory pathways. TCT-bound PGLYRP1 selectively impairs TREM-1 activation compared to PGNs from other bacteria. These findings demonstrate that B. pertussis co-opts PGLYRP1 to alter immune signaling, revealing a novel immune evasion mechanism with implications for vaccine design and host-directed therapeutics.