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Cutting Edge: A Common Polymorphism Impairs Cell Surface Trafficking and Functional Responses of TLR1 but Protects against Leprosy¹

Christopher M. Johnson^*,, Elizabeth A. Lyle^*, Katherine O. Omueti^,, Vitaly A. Stepensky^,, Olcay Yegin^¶, Erkan Alpsoy^||, Lutz Hamann^#, Ralf R. Schumann^# and Richard I. Tapping^2,*,

^* Department of Microbiology, Department of Biochemistry, Department of Cell and Developmental Biology, and College of Medicine, University of Illinois, Urbana, IL 61801; ^¶ Department of Pediatric Immunology and ^|| Department of Dermatology and Venerology, Akdeniz University School of Medicine, Akdeniz University, Antalya, Turkey; and ^# Institute of Microbiology and Hygiene, Charité-University Medical Center, Humboldt-University Berlin, Berlin, Germany

TLRs constitute an essential family of pattern recognition molecules that, through direct recognition of conserved microbial components, initiate inflammatory responses following infection. In this role, TLR1 enables host responses to a variety of bacteria, including pathogenic species of mycobacteria. In this study, we report that I602S, a common single nucleotide polymorphism within TLR1, is associated with aberrant trafficking of the receptor to the cell surface and diminished responses of blood monocytes to bacterial agonists. When expressed in heterologous systems, the TLR1 602S variant, but not the TLR1 602I variant, exhibits the expected deficiencies in trafficking and responsiveness. Among white Europeans, the 602S allele represents the most common single nucleotide polymorphism affecting TLR function identified to date. Surprisingly, the 602S allele is associated with a decreased incidence of leprosy, suggesting that Mycobacterium leprae subverts the TLR system as a mechanism of immune evasion.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Deutsche Forschungsgemeinschaft (to R.S.) and the National Institutes of Health, National Institute of Allergy and Infectious Diseases Grant AI052344 (to R.I.T.). Crude membrane fraction from Mycobacterium tuberculosis was obtained from Colorado State University under National Institute of Allergy and Infectious Diseases contract N01 AI75320.

² Address correspondence and reprint requests to Dr. Richard I. Tapping, Department of Microbiology, University of Illinois, B103 CLSL MC110, 601 South Goodwin Avenue, Urbana, IL 61801. E-mail address: tapping{at}life.uiuc.edu

³ Abbreviation used in this paper: SNP, single nucleotide polymorphism.

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