Clearance of group B streptococcal infection crucially depends on neutrophil recognition of two distinctive sets of bacterial formylated peptides (#209)

Background. Previous studies have highlighted the important role of toll-like receptors (TLRs) in neutrophil-mediated host defenses against group B streptococci (GBS). Little is known about the role of other innate immunity receptors. Methods. The role of formyl peptide receptor 1 (Fpr1) and 2 (Fpr2) was investigated using mice lacking these receptors in in vivo models of GBS infection or using in vitro stimulation of bone marrow-derived neutrophils. Results. Fpr1-/- or Fpr2-/- mice were more susceptible to GBS-induced peritonitis and sepsis relative to wild type mice, concomitantly with decreased production of the chemokine (CXC motif) ligand 2 (Cxcl2) and impaired neutrophil recruitment to infection sites. Exogenous administration of recombinant Cxcl2, but not Cxl1, rescued the phenotype of Fpr-deficient mice. In vitro, Fpr1 and Fpr2 were both required for robust production of reactive oxygen species (ROS) and of Cxcl2 by neutrophils stimulated with live GBS. Next, we identified two separate sets of GBS peptides that could induce Fpr1- and Fpr2-dependent activation, respectively. High-level Cxcl2 production was largely recapitulated by simultaneous stimulation of neutrophils with these peptides and TLR agonists. Mechanistically, Fpr- and TLR- activated signaling pathways converged at the level of the p38 MAPK, leading to robust activation of the AP-1 transcription factor. Conclusions. In neutrophils, full cell activation and robust bactericidal activity crucially depend on the integration of three types of signals originating from Fpr1, Fpr2 and TLRs, respectively, upon GBS stimulation. Concomitant activation of these receptors results in p38 MAPK-dependent, high-level production of Cxcl2 and ROS.