Impaired host defense to infection and Toll-like receptor 2-independent killing ofBorrelia burgdorfericlinical isolates in TLR2-deficient C3H/HeJ mice

Abstract

To investigate the role of Toll-like receptor 2 (TLR2)-mediated signaling in host innate defense and development of Lyme disease, the pathogenicity of Borrelia burgdorferi sensu stricto clinical isolates representing two distinct genotypes (RST1 and RST3A) was assessed in TLR2 3=3 C3H/HeJ mice. All TLR2 3=3 mice infected with a B. burgdorferi RST1 isolate developed severe arthritis. The numbers of spirochetes in heart, joint and ear biopsy specimens were significantly higher in TLR2 3=3 mice than in wild-type mice similarly infected as determined by real-time quantitative polymerase chain reaction. Interestingly, despite the higher spirochete levels in heart tissues, milder carditis was observed in TLR23=3 than in wild-type mice infected with this RST1 isolate (P = 0.02). By contrast, no positive cultures were obtained from any of the blood and tissue specimens from TLR2 3=3 mice inoculated with two RST3A clinical isolates. The data suggest that there is impaired host innate defense against infection and TLR2-independent killing of B. burgdorferi clinical isolates in TLR2-deficient C3H/HeJ mice.

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

“…These data support our findings that this SNP affects the recognition of triacylated, but not diacylated stimuli, because triacylated lipoproteins were described in Mycobacterium tuberculosis (42,43), while LTA from S. aureus is diacylated (31). Our finding that Arg753Gln protects from clinical symptoms of late stage infection with B. burgdorferi, including Lyme arthritis, appears to be in contrast to studies investigating TLR-2 and MyD88 knockout mice, because these animals displayed more severe arthritis than the corresponding wt mice (17)(18)(19)44), and mice heterozygous for TLR-2 did not differ from wt mice (17). However, arthritis in mice experimentally infected with B. burgdorferi is considered to be a subacute stage of disease, comparable to meningoencephalitis or myocarditis in humans, in which bacteria are present in the tissues, and we did not observe any association of subacute stages of LD with TLR-2 SNPs.…”

“…The causative role of IFN-␥ production for the development of arthritis in LD is in line with our hypothesis that lower levels of this and other cytokines protect from late stage LD, while acute and subacute stages are not affected. Furthermore, one study showed that, while arthritis was enhanced in TLR-deficient mice, carditis was less severe, indicating that an impaired recognition of B. burgdorferi may also have beneficial effects on the course of infection in these animals (44).…”

Pattern of Proinflammatory Cytokine Induction in RAW264.7 Mouse Macrophages Is Identical for Virulent and AttenuatedBorrelia burgdorferi

“…The expression of selected cytokine and related genes in mouse tissue and in RAW264.7 cells exposed to either isolate B356 or isolate BL206 was determined by real-time quantitative RT-PCR using SYBR Green technology with the LightCycler (Roche Applied Science) or the ABI 7900HT SDS (Applied Biosystems), as described previously (10,34,36). For each RNA sample, the expression of ␤-actin was quantified by real-time RT-PCR, and a ⌬⌬C t method was used to estimate the differential gene expression between samples (37).…”

Recognition of Borrelia burgdorferi, the Lyme Disease Spirochete, by TLR7 and TLR9 Induces a Type I IFN Response by Human Immune Cells

“…Spirochetal outer surface lipoproteins signal through TLR1/TLR2 heterodimers in a CD14-dependent manner, generating inflammatory mediators in Lyme disease patients, human monocytic cells, primate glial cells, mice and murine monocytes (12, 20 -26). TLR2 also functions in host defense, as TLR2 Ϫ/Ϫ mice harbor higher spirochete burdens in target tissues than wild-type controls (27,28). Recent reports have also established a role for TLR5, a receptor for bacterial flagellin, as a mediator of B. burgdorferi-induced inflammation in murine cells (12,25).…”