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. 2012;4(2):213-8.
doi: 10.1159/000329550. Epub 2011 Aug 19.

Importance of Toll-like Receptor 9 in Host Defense Against M1T1 Group A Streptococcus Infections

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Free PMC article

Importance of Toll-like Receptor 9 in Host Defense Against M1T1 Group A Streptococcus Infections

Annelies S Zinkernagel et al. J Innate Immun. .
Free PMC article

Abstract

Timely recognition and elimination of invasive group A Streptococcus (GAS) by innate immunity is crucial to control infection. The intracellular pattern recognition receptor Toll-like receptor 9 (TLR9) promotes macrophage hypoxia-inducible factor-1α levels, oxidative burst and nitric oxide production in response to GAS. TLR9 contributes to GAS clearance in vivo in both localized cutaneous and systemic infection models.

Figures

Fig. 1
Fig. 1
TLR9 is important for controlling GAS infection in vivo. a C57BL/6 (WT) and TLR9-deficient mice were injected subcutaneously with equivalent inocula of the M1 GAS strain, and skin lesion progression was measured for 4 days. b Representative photograph of skin lesions seen in the subcutaneous challenge experiment. c After 4 days, there were twice as many bacteria in the skin in the TLR9-deficient mice compared to the WT mice. d Using an intraperitoneal infection model, a subset of the mice (5 WT and 4 TLR9-deficient mice) were bled 24 h after GAS infection, and bacteremia was evaluated by serial dilution of the blood. e Survival of WT (n = 13) and TLR9-deficient (n = 12) mice followed over 1 week after intraperitoneal infection. Data are presented as means ± SEM. TLR9KO = TLR9-deficient.
Fig. 2
Fig. 2
TLR9 mediates killing of GAS by macrophages. a Surviving GAS after incubation with WT macrophages or TLR9-deficient macrophages at an MOI of 1, with and without the TLR9 antagonist G-ODN. b, c WT and TLR9-deficient macrophages were incubated with GAS at an MOI of 1, and ROS (b) and NO (c) was quantified. Data are given as box plots with n = 6 per point and 3 repeats (a) or as means ± SEM with n = 6 (b) and n = 3 (c) (representative experiment from 3 independent experiments). ANOVA was significant at p = 0.01, with Bonferroni pair-wise group comparison at * p < 0.05 and ** p < 0.005. TLR9KO = TLR9-deficient; OD = optical density at 540 nm.
Fig. 3
Fig. 3
TLR9 promotes HIF-1α expression. WT and TLR9-deficient macrophages were challenged with GAS. a Representative immunofluorescence micrograph. b Quantification of HIF-1α expression (infected cells, n = 14, images of 3 independent experiments; noninfected cells, n = 8, images of 2 independent experiments). c Nuclear extracts of the same cells were analyzed for HIF-1α expression by Western blot with analysis of β-actin as a loading control. Data are presented as means ± SEM. Scale bars = 100 μm. TLR9KO = TLR9-deficient; n.s. = not significant.

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