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Variable responses of formyl peptide receptor haplotypes toward bacterial peptides

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Abstract

The chemoattractant neutrophil formyl peptide receptor (FPR) binds bacterial and mitochondrial N-formylated peptides, which allows the neutrophils to find the bacterial source and/or site of tissue damage. Certain inflammatory disorders may be due in part to an impaired innate immune system that does not respond to acute bacterial damage in a timely fashion. Because the human FPR is encoded by a large number of different haplotypes arising from ten single-nucleotide polymorphisms, we examined the possibility that some of these haplotypes are functionally distinct. We analyzed the response of three common FPR haplotypes to peptides from Escherichia coli, Mycobacterium avium ssp. paratuberculosis, and human mitochondria. All three haplotypes responded similarly to the E. coli and mitochondrial peptides, whereas one required a higher concentration of the M. avium peptide fMFEDAVAWF for receptor downregulation, receptor signaling, and chemotaxis. This raises the possibility of additional bacterial species differences in functional responses among FPR variants and establishes a precedent with potentially important implications for our innate immune response against bacterial infections. We also investigated whether certain FPR haplotypes are associated with rheumatoid arthritis (RA) by sequencing FPR1 from 148 Caucasian individuals. The results suggested that FPR haplotypes do not significantly contribute toward RA.

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Acknowledgments

We thank Elena Suvorova and Bruce Granger for helpful discussions and Laura Richert and Britta Han for help in the laboratory. We thank Al Jesaitis, director of the Montana State University Blood Donor Program, for providing control blood samples. We thank Ms. Wendy McLaughlin (Bozeman Deaconess Hospital) for assistance with the RA blood samples and Jill Barker for help with statistical analysis. We also thank Laura Nelson, Dan Siemsen, and Mark Quinn for help with control blood samples. This project was funded in part by the National Institutes of Health grant R01 AI51726 (HMM), an American Heart Association Grant-in-Aid 0650153Z (HMM), and the National Institutes of Health grant R21DE16114 (JSM). The DNA sequencing was supported by National Institutes of Health grant P20 RR-016464 from the INBRE Program of the National Center for Research Resources (University of Nevada–Reno).

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Authors and Affiliations

  1. Department of Microbiology, Montana State University, 109 Lewis Hall, Bozeman, MT, 59717, USA

    Jeannie M. Gripentrog, John S. Mills & Heini M. Miettinen

  2. Bozeman Deaconess Health Group and WWAMI Medical Education Program, Montana State University, Bozeman, MT, 59717, USA

    George J. Saari

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  1. Jeannie M. Gripentrog
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  2. John S. Mills
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  4. Heini M. Miettinen
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Correspondence to Heini M. Miettinen.

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George J. Saari, Deceased.

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Gripentrog, J.M., Mills, J.S., Saari, G.J. et al. Variable responses of formyl peptide receptor haplotypes toward bacterial peptides. Immunogenetics 60, 83–93 (2008). https://doi.org/10.1007/s00251-008-0277-3

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