The formyl peptide receptor (FPR) is a G protein coupled receptor that is capable of binding formylated peptides that are indicative of the presence of bacteria. The sequence of FPR is highly polymorphic in the human population with no haplotype above 30% in gene frequency. Evaluations of patients with aggressive periodontitis have indicated that their neutrophils demonstrated poor chemotactic response toward the formyl peptide, methionine-leucine-phenylalanine (fMLP). Aggressive periodontitis (AgP) is a form of periodontitis that is characterized by a rapid rate of progression and a tendency toward familial aggregation. AgP is associated with neutrophil functional defects and infection by A. actinomycetemcomitans and Porphyromonas gingivalis. Recently genetic sequencing of the formyl peptide receptor from African Americans indicated that patients expressing the K192 polymorphism were associated with increased risk of aggressive periodontitis and that those expressing the W190 polymorphism were associated with reduced risk. This indicates that polymorphisms in FPR, which have been shown to be very common in the human population, may result in altered receptor function and that this altered function may result in increased risk of bacterial infections, especially A. actinomycetemcomitans associated endocarditis in children with congenital heart defects. We propose to test the hypothesis that the high degree of polymorphisms in FPR 1) evolved to allow the receptor to recognize the very large number of formyl peptides that are released from many different bacteria or 2) FPR polymorphisms evolved as a protection mechanism against pathogens capable of using FPR as a point of attachment, thereby reducing their virulence. We will evaluate FPR polymorphisms by preparing I11/R190/K192 FPR, I11/W190/N192 FPR, and T11/W190/N192 FPR. We will express them in CHO cells and compare their function to that of FPR- I11/R190/N192 and to each other. We will examine the polymorphisms for their ability to bind a wide rage of ligands to attempt to determine whether these polymorphisms result in alteration of ligand specificity, receptor desensitization and downregulation. In addition, we will evaluate them for altered chemotactic activity toward fMLP and the potent agonist fMMWLL.and determine their affinities for virally derived peptides.
| Gripentrog, Jeannie M; Mills, John S; Saari, George J et al. (2008) Variable responses of formyl peptide receptor haplotypes toward bacterial peptides. Immunogenetics 60:83-93 |
| Mills, John S (2007) Differential activation of polymorphisms of the formyl peptide receptor by formyl peptides. Biochim Biophys Acta 1772:1085-92 |
| Mills, John S (2006) Peptides derived from HIV-1, HIV-2, Ebola virus, SARS coronavirus and coronavirus 229E exhibit high affinity binding to the formyl peptide receptor. Biochim Biophys Acta 1762:693-703 |
