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Toll-like receptor 2 participates in mediation of immune response in experimental pneumococcal meningitis
Uwe Koedel1, Barbara Angele, Tobias Rupprecht
1Department of Neurology, Klinikum Grosshadern, Ludwig-Maximilians University, Munich, Germany.
Abstract:
Heterologous expression of Toll-like receptor (TLR)2 and CD14 in Chinese hamster ovary fibroblasts was reported to confer responsiveness to pneumococcal peptidoglycan. The present study characterized the role of TLR2 in the host immune response and clinical course of pneumococcal meningitis. Pneumococcal infection of mice caused a significant increase in brain TLR2 mRNA expression at both 4 and 24 h postchallenge. Mice with a targeted disruption of the TLR2 gene (TLR2-/-) showed a moderate increase in disease severity, as evidenced by an aggravation of meningitis-induced intracranial complications, a more pronounced reduction in body weight and temperature, and a deterioration of motor impairment. These symptoms were associated with significantly higher cerebellar and blood bacterial titers. Brain expression of the complement inhibitor complement receptor-related protein y was significantly higher in infected TLR2-/- than in wild-type mice, while the expression of the meningitis-relevant inflammatory mediators IL-1beta, TNF-alpha, IL-6, macrophage-inflammatory protein (MIP)-2, inducible NO synthase, and C3 was similar in both genotypes. We first ectopically expressed single candidate receptors in HEK293 cells and then applied peritoneal macrophages from mice lacking TLR2 and/or functional TLR4 for further analysis. Overexpression of TLR2 and TLR4/MD-2 conferred activation of NF-kappaB in response to pneumococcal exposure. However, pneumococci-induced TNF-alpha release from peritoneal macrophages of wild-type and TLR2/functional TLR4/double-deficient mice did not differ. Thus, while TLR2 plays a significant role in vivo, yet undefined pattern recognition receptors contribute to the recognition of and initiation of the host immune defense toward Streptococcus pneumoniae infection.
Insights
Toll-like receptor 2 (TLR2) plays a significant role in the immune response to pneumococcal meningitis. Mice lacking TLR2 exhibited increased disease severity and bacterial load, indicating its importance in host defense.
Area of Science:
- Immunology
- Microbiology
- Neuroscience
Background:
- Toll-like receptor 2 (TLR2) and CD14 mediate responses to pneumococcal peptidoglycan.
- The role of TLR2 in pneumococcal meningitis pathogenesis requires further characterization.
Purpose of the Study:
- To investigate the function of TLR2 in the host immune response to Streptococcus pneumoniae infection.
- To determine the impact of TLR2 deficiency on the clinical course and severity of pneumococcal meningitis.
Main Methods:
- Mice with targeted disruption of the TLR2 gene (TLR2-/-) were infected with Streptococcus pneumoniae.
- Brain TLR2 mRNA expression was analyzed post-infection.
- Disease severity, intracranial complications, body weight, temperature, motor impairment, and bacterial titers were assessed.
- Expression of inflammatory mediators and complement inhibitors was measured.
- HEK293 cells and peritoneal macrophages from TLR2/TLR4 deficient mice were used for in vitro analysis of NF-kappaB activation and TNF-alpha release.
Main Results:
- Pneumococcal infection significantly increased brain TLR2 mRNA expression.
- TLR2-/- mice showed aggravated meningitis, reduced body weight and temperature, motor impairment, and higher bacterial titers.
- Expression of complement receptor-related protein y was elevated in infected TLR2-/- mice.
- Expression of key inflammatory mediators (IL-1beta, TNF-alpha, IL-6, MIP-2, iNOS, C3) was similar between genotypes.
- Overexpression of TLR2 and TLR4/MD-2 activated NF-kappaB in response to pneumococci.
- Pneumococci-induced TNF-alpha release did not differ between wild-type and double-deficient macrophages.
Conclusions:
- TLR2 plays a significant role in vivo during pneumococcal meningitis, influencing disease severity and bacterial clearance.
- Despite TLR2's importance, other, yet undefined, pattern recognition receptors contribute to the host's initial defense against Streptococcus pneumoniae.
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