Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients

Abstract

Toll-like receptor 2 (TLR2) is critical in the immune response to mycobacterial infections and the mutations in the TLR2 have been shown to confer the susceptibility to severe infection with mycobacteria. To define this, we screened the intracellular domain of TLR2 in 131 subjects. Groups of 45 lepromatous and 41 tuberculoid leprosy (TT) patients and 45 controls were investigated. Ten subjects among the lepromatous leprosy (LL) patients had a band variant detected by single-stranded conformational polymorphism. DNA sequencing detected a C to T substitution at nucleotide 2029 from the start codon of the TLR2. The mutation would substitute Arg to Trp at amino acid residue 677, one of the conserved regions of TLR2. In our results, the mutation was involved in only LL, not TT and control. Thus, we suggest that the mutation in the intracellular domain of TLR2 has a role in susceptibility to LL.

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 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). Both mutations are located at the C-terminus of the TLR2, in the TIR .…”

“…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

“…76 In this study, patients were categorized as having one of the two major disease patterns, tuberculoid (characterized by few bacteria and a pronounced cell-mediated host response) and lepromatous (characterized by a large bacillary load and relatively weak host immune response). Ten of 45 (22%) of the lepromatous patients exhibited a C-T transition at nucleotide 2029, resulting in replacement of a conserved arginine residue with tryptophan at amino acid 677, while none of the tuberculoid patients nor control group carried this mutation.…”

Polymorphisms in Toll-like receptors-2 and -4 are not associated with disease manifestations in acute Q fever

“…3,4 There is evidence for a role for both TLR-2 and -4 in Coxiella-macrophage interactions, including recognition, phagocytosis and intracellular survival. 5,6 Functional polymorphisms in the human TLR-2 gene (Arg677Trp and Arg753Gln) have been associated with the mycobacterial infections, tuberculosis and leprosy, 7,8 and in the TLR-4 (Asp299Gly) gene with Gram-negative sepsis. 9 We examined these polymorphisms and their functional significance in 85 subjects with acute Q fever and 162 control subjects with unrelated viral infections.…”