J. Exp. Med., Volume 189, Number 4, February 15, 1999 657-662

Impaired Antibacterial Host Defense in Mice Lacking the N-formylpeptide Receptor

By Ji-Liang Gao,^* Eric J. Lee, and Philip M. Murphy^*

From the ^* Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, and the  Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

N-formylpeptides derive from bacterial and mitochondrial proteins, and bind to specific receptors on mammalian phagocytes. Since binding induces chemotaxis and activation of phagocytes in vitro, it has been postulated that N-formylpeptide receptor signaling in vivo may be important in antimicrobial host defense, although direct proof has been lacking. Here we test this hypothesis in mice lacking the high affinity N-formylpeptide receptor (FPR), created by targeted gene disruption. FPR^/ mice developed normally, but had increased susceptibility to challenge with Listeria monocytogenes, as measured by increased mortality compared with wild-type littermates. FPR^/ mice also had increased bacterial load in spleen and liver 2 d after infection, which is before development of a specific cellular immune response, suggesting a defect in innate immunity. Consistent with this, neutrophil chemotaxis in vitro and neutrophil mobilization into peripheral blood in vivo in response to the prototype N-formylpeptide fMLF (formyl-methionyl-leucyl-phenylalanine) were both absent in FPR^/ mice. These results indicate that FPR functions in antibacterial host defense in vivo.

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