Enemy attraction: bacterial agonists for leukocyte chemotaxis receptors

Key Points Recognition of invading bacteria is a crucial task for the human innate immune system to initiate the first line of defence against infections. For this purpose various receptors have evolved, each with different specificities for conserved microbial molecules. One important function of these receptors is to promote the migration of immune cells to the centre of infection along a gradient of microbial- or host-derived chemoattractants. This mechanism is called chemotaxis and is a crucial prerequisite for the elimination of pathogens. Certain bacterial peptides can function as potent leukocyte attractants. Owing to the characteristics of bacterial translation, bacterial proteins are synthesized with a formylated methionine at the amino terminus. This feature is exploited by the human innate immune system because formylated peptides are identified as chemokines for leukocytes. The chemoattractant receptor repertoire is limited and comprises members of the family of G protein-coupled receptors (GPCRs). Among them, the human formyl peptide receptor 1 (FPR1) is specialized to detect formylated peptides. Among the two orthologues of FPR1, only FPR2 has been confirmed to detect microbial peptides; FPR2 also detects endogenous ligands. Recently, particular interest in FPR2 has arisen owing to the description of bacterial FPR2 ligands. These include the phenol-soluble modulin (PSM) peptides, which are cytotoxic at high concentrations and are secreted by Staphylococcus aureus and other staphylococci. FPR2 was further shown to respond differently to pathogenic and non-pathogenic staphylococcal strains according to the production of PSMs. In addition to staphylococci, other bacteria such as Helicobacter pylori or enterococci activate FPR2. However, only in some instances has the nature of the agonists been identified. Short-chain fatty acids are products of the energy metabolism of fermenting bacteria. They are recognized by the GPCRs GPR41 and GPR43 to mediate neutrophil chemotaxis and contribute to intestinal epithelial homeostasis. Bacteria have evolved strategies to evade the host response by synthesizing molecules that block chemokine receptors. The recognition of bacterial chemotactic molecules may be beneficial for the host or, in some instances, also for pathogens taking advantage of inflammation. Moreover, chemotactic molecules are not only crucial for infection, they are also secreted by commensal bacteria and regulate epithelial homeostasis in th