Heterozygous Arg753Gln Polymorphism of Human TLR-2 Impairs Immune Activation by Borrelia burgdorferi and Protects from Late Stage Lyme Disease

Abstract

Lyme disease (LD) is caused by Borrelia burgdorferi and displays different stages, including localized, early disseminated, and persistent infection, all of which are associated with profound inflammatory reactions in the host. Induction of proinflammatory cytokines by B. burgdorferi is mainly mediated by outer surface proteins interacting with TLR-2/TLR-1 heterodimers. In this study, we show that TNF-α induction by Borrelia lysate was impaired in heterozygous TLR-2 knockout mice, while reactivity to lipoteichoic acid, another TLR-2 ligand signaling via TLR-2/TLR-6 heterodimers, was unaffected. Blood from individuals heterozygous for the TLR-2 polymorphism Arg753Gln was tested for cytokine release upon stimulation with Borrelia lysate, and induction of TNF-α and IFN-γ was significantly lower as compared with individuals not exhibiting this variation. Overexpression of TLR-2 carrying the Arg753Gln polymorphism in HEK 293 cells led to a significantly stronger impairment of activation by TLR-2/TLR-1 ligands as compared with TLR-2/TLR-6 ligands. To study whether heterozygosity for the Arg753Gln variant of TLR-2 influenced susceptibility for LD, we analyzed 155 patients for this polymorphism. The Arg753Gln variant occurs at a significantly lower frequency in LD patients as compared with matched controls (5.8 vs 13.5%, odds ratio 0.393, 95% confidence interval 0.17–0.89, p = 0.033), with an even more pronounced difference when late stage disease was observed (2.3 vs 12.5%, odds ratio 0.163, 95% confidence interval 0.04–0.76, p = 0.018). These data suggest that Arg753Gln may protect from the development of late stage LD due to a reduced signaling via TLR-2/TLR-1.

Structural and Functional Evidence for the Role of the TLR2 DD Loop in TLR1/TLR2 Heterodimerization and Signaling

“…Notably, polymorphism of residue Arg-753 (R753Q) has been linked with the susceptibility to Staphylococcal, Borellia sp., and Mycobacterium sp. and has also been associated with acute rheumatoid fever in children (23)(24)(25)(26)(27). Thus our modeling studies also suggest a potential explanation for the observed decreased activity of the R753Q polymorphism.…”

Toll-Like Receptors: Sentinels of Host Defence against Bacterial Infection

“…The TLR2 polymorphism R753Q may predispose to infection with S. aureus [102] or M. tuberculosis [103]. Finally in a very recent publication, it was demonstrated that the same R753Q polymorphism in TLR2 protects from late-stage Lyme disease [104]. Collectively, these human studies have confirmed the important role that TLRs play in a protective immune response and are generally consistent with the information obtained from gene-deficient mice.…”

Overview and Outlook of Toll-like Receptor ligand–antigen Conjugate Vaccines

“…Several SNPs have been associated not only with cancer risk [17] but also a susceptibility to several diseases, such as HIV infection [18,19], urinary tract infections (cystitis and pyelonephritis) [20], Hansen's disease [21,22], Lyme disease [23], Legionnaires' disease [24,25], asthma [26,27], atopic syndrome [27], sepsis [28] and tuberculosis [29]. In addition, cellular studies have revealed the effect of TLR polymorphisms on TLR ligand-induced innate immune responses.…”