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

The bacterium Bordetella pertussis, responsible for whooping cough, continues to pose a significant public health threat despite widespread vaccination efforts. To combat this persistent issue, researchers are investigating potential improvements to therapeutics and vaccines. Host recognition of bacterial peptidoglycan (PGN) and its fragments, such as tracheal cytotoxin (TCT) found in B. pertussis, plays a crucial role in shaping the immune response to infection.

Peptidoglycan recognition proteins (PGLYRPs) are a family of proteins known for their bactericidal activity in mammals; however, their role in modulating immune responses is gaining attention. The impact of PGLYRPs on host defenses against Gram-negative pathogens like B. pertussis remains unclear. To address this gap, scientists employed knockout mice, single-cell and bulk transcriptomics, and functional assays to uncover a dual role for PGLYRP1 in immune responses to B. pertussis.

PGLYRP1 contributes to antibacterial defenses but simultaneously dampens inflammatory responses, inhibiting bacterial killing later in the infection process. Mechanistically, PGLYRP1 enhances NOD1 signaling upon encountering TCT while suppressing NOD2- and TREM-1-mediated inflammatory pathways. Importantly, TCT-bound PGLYRP1 selectively inhibits TREM-1 activation compared to PGNs from other bacteria.

These findings reveal that B. pertussis can manipulate PGLYRP1 to alter immune signaling, unveiling a novel immune evasion mechanism with important implications for vaccine development and host-directed therapeutic strategies.