Neutrophils Discriminate between Live and Dead Bacteria By a Three-Signal Mechanism Involving Formyl Peptide and Toll-Like Receptors

The host defense system continuously monitors pathogen viability during infection and regulates its functions accordingly. Neutrophils, which are the body’s first line of defense, become more vigorously activated in the presence of live, compared with killed bacteria, but the mechanisms underly ing these differential responses are unclear. Neutrophils can self-regulate their activation status by producing the chemokine Cxcl2, which acts autocrinuonsly to amplify their recruitment to infection sites and their bactericidal functions. We prove that neutrophils produce 5- to 30-fold higher levels of Cxcl2 in response to live bacteria, compared with killed bacteria.  The signal is provided by protein synthesis and secretion in live bacteria of two separate sets of formylated signal peptides.  Peptides selectively activate formylated peptide receptor 1 or 2 (Fpr1 or Fpr2).  We demonstrate that the  agonists for Fpr1, Fpr2 and Toll-like receptors represents a unique signature associated with viable bacteria.