Peptidoglycan recognition protein 4 suppresses early inflammatory responses to Bordetella pertussis and contributes to S1PR agonist-mediated disease attenuation.

Incidence of whooping cough (pertussis), a bacterial infection of the respiratory tract caused by the bacterium Bordetella pertussis , has reached levels not seen since the 1950s. Antibiotics fail to improve the course of disease unless administered early in infection. Therefore, there is an urgent need for the development of anti-pertussis therapeutics. Sphingosine-1-phosphate receptor (S1PR) agonists have been shown to reduce pulmonary inflammation during Bordetella pertussis infection in mouse models. However, the mechanisms by which S1PR agonists attenuate pertussis disease are unknown. We report the results of an RNAseq study examining pulmonary transcriptional responses in B. pertussis -infected mice treated with S1PR agonist AAL-R or vehicle control. This study identified peptidoglycan recognition protein 4 (PGLYRP4) as one of the most highly upregulated genes in the lungs of infected mice following S1PR agonism. PGLYRP4, a secreted, innate mediator of host defenses was found to limit early inflammatory pathology in knock-out mouse studies. Further, S1PR agonist AAL-R failed to attenuate pertussis disease in PGLYRP4 KO mice. B. pertussis virulence factor tracheal cytotoxin (TCT), a secreted peptidoglycan breakdown product, induces host tissue damage. TCT over-secreting strains were found to drive an early inflammatory response similar to that observed in PGLYRP4 KO mice. Further, TCT over-secreting strains induced significantly greater pathology in PGLYRP4 deficient animals than their wild-type counterparts. Together these data indicate that S1PR agonist mediated protection against pertussis disease is mediated via PGLYRP4. Our data suggest PGLYRP4 functions, in part, by preventing TCT induced airway damage.