N-formylpeptides are phagocyte chemoattractants that act by binding to two structurally related receptors, FPR (formylpeptide receptor) and FPRL1R (FPR-like-1 receptor), which are encoded by the human genes FPR1 and FPRL1. Single nucleotide polymorphisms (SNPs) in the FPR coding region have been reported and two have been associated with the disease juvenile periodontitis; however, their frequency and linkage relationships are unknown. Here we systematically analyzed polymorphism in the open reading frames of FPR1 and FPRL1 by direct sequencing of cloned alleles from random blood donors from North America. For FPR1 we detected five non-synonymous SNPs and two synonymous SNPs in a sample of 26 chromosomes one each from 17 Caucasian and nine black random blood donors. Although all five non-synonymous SNPs were common in Caucasians, Blacks, and Asians, notable differences in allele frequency were found for each SNP in the different racial groups, suggesting differential selective pressures. We found that the FPR1 polymorphisms are linked in 15 common haplotypes. No polymorphisms were detected in FPRL1 after sampling 44 chromosomes from 36 random blood donors from the same three racial groups. Thus FPR1 and FPRL1, though they originated from a common gene, appear to have undergone markedly different evolutionary events.

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The opportunistic fungal pathogen Aspergillus fumigatus can cause severe infections, particularly in immunocompromised individuals. Upon infection, A. fumigatus faces the powerful and directly acting immune defense of the human host. The mechanisms on how A. fumigatus evades innate immune attack and complement are still poorly understood. Here, we identify A. fumigatus enolase, AfEno1, which was also characterized as fungal allergen, as a surface ligand for human plasma complement regulators. AfEno1 binds factor H, factor-H-like protein 1 (FHL-1), C4b binding protein (C4BP), and plasminogen. Factor H attaches to AfEno1 via two regions, via short conserved repeats (SCRs) 6–7 and 19–20, and FHL-1 contacts AfEno1 via SCRs 6–7. Both regulators when bound to AfEno1 retain cofactor activity and assist in C3b inactivation. Similarly, the classical pathway regulator C4BP binds to AfEno1 and bound to AfEno1; C4BP assists in C4b inactivation. Plasminogen which binds to AfEno1 via lysine residues is accessible for the tissue-type plasminogen activator (tPA), and active plasmin cleaves the chromogenic substrate S2251, degrades fibrinogen, and inactivates C3 and C3b. Plasmin attached to swollen A. fumigatus conidia damages human A549 lung epithelial cells, reduces the cellular metabolic activity, and induces cell retraction, which results in exposure of the extracellular matrix. Thus, A. fumigatus AfEno1 is a moonlighting protein and virulence factor which recruits several human regulators. The attached human regulators allow the fungal pathogen to control complement at the level of C3 and to damage endothelial cell layers and tissue components.

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