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The Polymorphism P315L of Human Toll-Like Receptor 1 Impairs Innate Immune Sensing of Microbial Cell Wall Components¹

Katherine O. Omueti^*,, Daniel J. Mazur, Katherine S. Thompson, Elizabeth A. Lyle and Richard I. Tapping^2,,

^* Department of Biochemistry, Department of Microbiology, and College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801

As a pattern recognition receptor, TLR1 mediates innate immune responses to a variety of microbial cell wall components including bacterial lipoproteins. We have previously shown that the central region of the extracellular domain of human TLR1, comprising leucine-rich repeat (LRR) motifs 9–12, is required for the sensing of bacterial lipopeptides. In this study, we have investigated three nonsynonymous single nucleotide polymorphisms (SNPs) located in this region of TLR1 by generating these variants and examining receptor function. We have found that a variant of TLR1 based upon the SNP P315L, located in the loop of LRR motif 11 (LRR11), is greatly impaired in mediating responses to lipopeptides and a variety of other bacterial agonists for this receptor. Despite normal cell surface expression, the P315L variant also fails to bind to GD2.F4, a commonly used anti-TLR1 mAb. Although a number of amino acid substitutions at position 315 impair receptor function, the leucine substitution has the strongest deleterious effect. GD2.F4 inhibits agonist-induced activation of TLR1, supporting a crucial role for the loop of LRR11 in receptor function. These results also suggest that the P315L SNP may predispose certain individuals to infectious diseases for which the sensing of microbial cell components by TLR1 is critical to innate immune defense.

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 start-up funds from the University of Illinois as well as National Institutes of Health Grant AI052344 (to R.I.T.).

² Address correspondence and reprint requests to Dr. Richard I. Tapping, Department of Microbiology, B103 Chemical and Life Science Building, MC 110, 601 South Goodwin Avenue, Urbana, IL 61801. E-mail address: tapping{at}life.uiuc.edu

³ Abbreviations used in this paper: ECD, extracellular domain; Pam₃CSK₄, N-palmitoyl-S-[2,3-bis(palmitoyloxy)-propyl]-(R)-cysteinyl-(lysyl)3-lysine; PamCysPamSK₄, N-palmitoly-S-[2-hydroxy-3-(palmitoyloxy)propyl]-(R)-cysteinyl-(lysyl)3-lysine; LRR, leucine rich repeat; LRR11, LRR motif 11; SNP, single nucleotide polymorphism.