A Novel Polymorphism in the Toll-Like Receptor 2 Gene and Its Potential Association with Staphylococcal Infection

Abstract

The toll-like receptor 2 (TLR2) has gained importance as a major mammalian receptor for lipoproteins derived from the cell wall of a variety of bacteria, such as Borrelia burgdorferi, Treponema pallidum, and Mycoplasma fermentans. We were interested in identifying mutations in the TLR2 gene that might prove to be associated with altered susceptibility to septic shock. We performed a mutation screen of the TLR2 gene using single-stranded conformational polymorphism in 110 normal, healthy study subjects and detected an Arg753Gln mutation in three individuals. No other missense mutations were detected in the TLR2 open reading frame. Functional studies demonstrate that the Arg753Gln polymorphism, in comparison to the wild-type TLR2 gene, is significantly less responsive to bacterial peptides derived from B. burgdorferi and T. pallidum. In a septic shock population, the Arg753Gln TLR2 polymorphism occurred in 2 out of 91 septic patients. More importantly, both of the subjects with the TLR2 Arg753Gln polymorphism had staphylococcal infections. These findings suggest that a mutation in the TLR2 gene may predispose individuals to lifethreatening bacterial infections.Microbial pathogens are a major health concern worldwide. Invasion of the host by microbial pathogens causes the activation of the innate immune response, which acts as a first line of defense against pathogenic bacteria. The innate immune response triggers a sequence of events that results in the production and secretion of cytokines and chemokines, activation of macrophages and monocytes, and in some cases initiation of adaptive immunity (10).The toll receptors appear to be very important in initiating the innate immune response. C3H/HeJ mice which have a mutation in the toll-like receptor 4 (TLR4) gene (Pro712His) and C57BL6/10ScCr mice which have a deletion of TLR4 are both hyporesponsive to lipopolysaccharide (LPS) (12). The TLR4 mutation in C3H/HeJ mice was the first direct proof for identifying TLR4 as a major LPS receptor in mammals. Subsequently TLR4 Ϫ/Ϫ mice were shown to be LPS hyporesponsive as well (6). Binding of LPS to TLR4, via a complex involving CD14 as well as MD-2, is thought to initiate a signaling cascade that involves several kinases and accessory molecules such as MyD88 and IRAK, leading eventually to a nuclear translocation of transcription factors NF-B and AP-1 (14). The binding of these transcription factors is responsible for initiating cytokine and chemokine expression subsequent to LPS exposure. Recently, mutations in the TLR4 receptor at residues 299 and 399 were shown to be associated with hyporesponsiveness to inhaled endotoxin in humans (2). Furthermore, the Asp299Gly TLR4 mutation may increase the risk to carriers of developing gram-negative septic shock (E. Lorenz, J. Mira, K. Frees, and D. Schwartz, submitted for publication). However, TLR4 does not seem to be involved in mediating the cellular response to gram-positive pathogens. TLR2, which is highly homologous to TLR4, has been shown to mediate a response to LPS, albei...

Susceptibility to paratuberculosis infection in cattle is associated with single nucleotide polymorphisms in Toll-like receptor 2 which modulate immune responses against Mycobacterium avium subspecies paratuberculosis

“…Two mutations in TLR2, an Arg753Gln polymorphism and an Arg677Trp polymorphism, have been associated with susceptibility to disease (Lorenz et al, 2000;Kang and Chae, 2001). The Arg753Gln polymorphism has been associated with a negative influence on TLR2 signalling, increasing the risk of mycobacterial infections (Mycobacterium leprae and Mycobacterium tuberculosis) as well as infections with Gram-positive (Staphylococcus aureus) and Gram-negative (Borrelia burgdorferi) bacteria (Lorenz et al, 2000;Ogus et al, 2004). The Arg677Trp mutation is probably involved in determining the type of leprosy, because it was significantly more prevalent in patients with lepromatous leprosy than with tuberculoid leprosy (Kang and Chae, 2001;Ben-Ali et al, 2004).…”

“…We hypothesize that inefficient recognition of Map and failure in the subsequent innate and adaptive immune responses can be caused by defects in genes coding for TLR. TLR2 has been described as one of the main receptors for mycobacteria, and in humans, mutations in TLR2 have been detected and associated with higher susceptibility to tuberculosis (Lorenz et al, 2000;Kang and Chae, 2001;Ogus et al, 2004). After uptake, Map is able to evade the destructive processes by inhibition of phagolysosome fusion and is able to replicate inside the macrophages (Kuehnel et al, 2001;Hostetter et al, 2003;Weiss et al, 2004) and possibly also inside DC.…”

Toll-like receptors and their role in experimental models of microbial infection

“…64 A mutation (Arg753Gln) within a group of highly conserved amino acids at the C-terminus of TLR2 was identified in 3% of healthy blood donor controls; transfection of this mutant into human epithelial kidney (HEK 293T) cells revealed decreased cellular activation in response to bacterial lipoproteins but not LPS. The Arg753Gln TLR2 variant was identified in two of 91 patients with septic shock; while this association was not statistically significant, both patients bearing the polymorphism were infected with S. aureus, suggesting that it may be a predisposing factor for severe Gram-positive infection.…”

CD14 promoter polymorphism −159C>T is associated with susceptibility to chronic Chlamydia pneumoniae infection in peripheral blood monocytes

“…Previously, enhanced frequencies of the Arg753Gln TLR2 and Asp299Gly TLR4 polymorphisms were found in patients with staphylococcal sepsis or Gram-negative infections in critically ill patients. 9,10 We thus examined whether the chronic C. pneumoniae infection in coronary artery disease (CAD) patients is related to the prevalence of these genetic variations in TLR2, TLR4 or CD14. We focused on 78 CAD patients determined to be chronically infected with C. pneumoniae as defined by consistent detection of C. pneumoniae DNA in their PBMC fraction up to 1 year.…”