Cutting Edge: A Toll-Like Receptor 2 Polymorphism That Is Associated with Lepromatous Leprosy Is Unable to Mediate Mycobacterial Signaling

Abstract

Toll-like receptors (TLRs) are key mediators of the innate immune response to microbial pathogens. We investigated the role of TLRs in the recognition of Mycobacterium leprae and the significance of TLR2Arg677Trp, a recently discovered human polymorphism that is associated with lepromatous leprosy. In mice, TNF-α production in response to M. leprae was essentially absent in TLR2-deficient macrophages. Similarly, human TLR2 mediated M. leprae-dependent activation of NF-κB in transfected Chinese hamster ovary and human embryonic kidney 293 cells, with enhancement of this signaling in the presence of CD14. In contrast, activation of NF-κB by human TLR2Arg677Trp was abolished in response to M. leprae and Mycobacterium tuberculosis. The impaired function of this TLR2 variant provides a molecular mechanism for the poor cellular immune response associated with lepromatous leprosy and may have important implications for understanding the pathogenesis of other mycobacterial infections.

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

“…Bochud et al (2003) have shown that the Arg677Trp mutation prohibits the Toll-pathway and production of NFkB. Although the mutations found in the current study are not in the intra-cellular C-terminus of TLR2, the results indicate that the mutations in the extracellular LRR also influence TLR2 signalling and production of NFkB.…”

Staphylococcus aureus protein A induced inflammatory response in human corneal epithelial cells

“…Under normal circumstances, the cornea is highly impermeable to pathogens due to intact epithelium, however when the epithelial barrier is broken such as due to contact lens wearing or trauma [13], the bacteria gain access to the ocular surface, resulting in their intracellular multiplication and severe inflammation, leading to keratitis. Because SpA is a major surface protein present in almost all strains of S. aureus we reasoned that it is likely to possess ability to interact with and trigger epithelial response, contributing corneal inflammation and pathogenesis [14]. Indeed, we showed that SpA induced an inflammatory response in HCECs.…”

Innate immunity conferred by toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation

“…Since the acute inflammatory responses to CPPD crystals resemble those of MSU crystals, we speculate that TLR-2, TLR-4, and MyD88 could also mediate CPPD crystal-induced acute inflammation. Finally, TLR-2 and TLR-4 sequence variants have been linked to altered microbial carriage and phenotypic response of the host to infection (54,55). Hence, it will be of interest to determine if inherited or acquired alterations in the structure and function of TLR-2 and TLR-4 contribute to variability in the clinical phenotype of gout in humans with hyperuricemia (1).…”