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

Peptidoglycan recognition protein 1 (PGLYRP1) is a secreted antimicrobial protein. However, its role in mammalian host defenses and immune signaling during infection with Gram-negative pathogens, such as B. pertussis, remain largely unknown. Here, we identify a dual role for PGLYRP1 in modulating host immune responses to B. pertussis.

Using knockout mice, single-cell and bulk transcriptomics and functional assays, we show that PGLYRP1 has bactericidal activity against B. pertussis in vitro and promotes early bacterial control in vivo. PGLYRP1 also dampens inflammatory responses and impedes bacterial killing later in infection. Mechanistically, PGLYRP1 enhances nucleotide oligomerization domain (NOD)-1 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, revealing a novel bacterial immune evasion strategy. These findings demonstrate that B. pertussis co-opts PGLYRP1 to temper inflammation and alter immune signaling, revealing a novel immune evasion mechanism of manipulating the availability and structure of their exogenous peptidoglycan, revealing implications for host-pathogen evolution, vaccine design and host-directed therapeutics.