ABSTRACT Yersinia pestis, the plague agent, caused major pandemics, reiteratively killing most of the human population. The extraordinary mortality of plague is thought to have shaped the human immune system, however its genetic imprint was not known. Y. pestis employs a virulence-plasmid encoded type III secretion system (T3SS) to kill immune cells, thereby replicating unencumbered in the bloodstream of infected hosts. Of particular importance is LcrV, the plague-protective antigen and needle-cap protein of the T3SS, which enables transport of Yersinia effectors (Yops) into immune cells. To identify the human plague receptor for Y. pestis T3SS, we screened for inhibitors that interfere with effector translocation. Ligands of formyl-peptide receptor 1 (FPR1) and antibodies against FPR1 block Y. pestis T3SS injection into human primary neutrophils and cultured immune cells. CRISPR-Cas9 mutagenesis demonstrated that FPR1 is essential for Y. pestis T3SS- mediated killing of human monocytes. Pulldown of tagged FPR1 from Y. pestis infected macrophages revealed the association between FPR1 and T3SS needle complexes, which are comprised of LcrV and YopD. These findings establish FPR1, a G-protein coupled receptor that activates chemotaxis in response to N- formylpeptides or annexin 1 signaling, as the plague receptor on human immune cells. In wild-type mice, plague infection is characterized by Y. pestis T3SS-induced obliteration of the immune system and high mortality, whereas N-formylpeptide receptor deficient (mFpr1-/-) mice exhibit delayed time-to-death, increased survival and the development of protective immunity. Immune cells of mFpr1-/- mice are partially resistant to T3SS and defective for chemotaxis towards Y. pestis. Human FPR1 is a polymorphic gene. Single nucleotide polymorphisms (SNPs) are more frequent in FPR1 than in other human genes. Screening neutrophils of human volunteers for resistance to Y. pestis T3SS, we identified FPR1R190W as a candidate resistance allele. This proposal explores the molecular mechanisms linking Y. pestis T3SS and LcrV with human FPR1 and other host factors to gain deep understanding into the pathogenesis of plague and the mechanisms that shaped FPR1 and human immune responses. Other work will characterize the plague receptor on immune cells of mice, testing the hypothesis that mutations in FPR1 confer resistance to plague disease. N- formylpeptide receptors of different animal species will be characterized to understand plague susceptibility and resistance in mammals.