Innate immunity to pneumococcal infection of the central nervous system depends on Toll-like receptor (TLR) 2 and TLR4
Innate immunity to pneumococcal infection of the central nervous system depends on Toll-like receptor (TLR) 2 and TLR4
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DOI：
10.1086/591626
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发表时间：
2008-10-01
影响因子：
6.4
通讯作者：
Kirschning, Carsten J.
中科院分区：
文献类型：
--
作者：
Klein, Matthias;Obermaier, Bianca;Kirschning, Carsten J.
背景最近的研究表明，除了Toll样受体（TLR）2外，其他模式识别受体介导肺炎链球菌（SP）感染中枢神经系统（CNS）后免疫应答的激活。利用小鼠脑膜炎模型，我们研究了TLR 4单缺陷（TLR 4（-/-））、TLR 2/TLR 4双缺陷（TLR 2/4（-/-））和TLR 2/TLR 4/TLR 9三缺陷（TLR 2/4/9（-/-））对CNS对SP感染的免疫应答的影响。为了鉴定介导SP应答的细胞群，我们制备了TLR 2/4（-/-）-野生型（wt）骨髓（BM）嵌合体。与感染的野生型小鼠相比，感染的TLR 2/4（-/-）和TLR 2/4/9（-/-）小鼠在脑细胞因子水平、白细胞增多和脑病理学发现方面具有相似的降低，而在感染的TLR 4（-/-）小鼠中没有观察到这种作用。减弱的免疫应答被受损的宿主防御所抵消，导致疾病恶化。感染后嵌合体小鼠的分析表明，无论是放射抗性细胞还是移植的BM衍生细胞，仅TLR 2/4缺陷就足以引起实质性的脑免疫应答，如在野生型小鼠中所注意到的。在小鼠SP脑膜炎中，TLR 2和TLR 4表达于放射抗性和移植的BM衍生细胞上，是入侵SP诱导炎症反应的主要细胞传感器。
Background. Recent studies have suggested that, in addition to Toll-like receptor (TLR) 2, other pattern recognition receptors mediate activation of the immune response after infection of the central nervous system (CNS) with Streptococcus pneumoniae (SP).Methods. Using a mouse meningitis model, we investigated the influence of TLR4 single deficiency (TLR4(-/-)), TLR2/TLR4 double deficiency (TLR2/4(-/-)), and TLR2/TLR4/TLR9 triple deficiency (TLR2/4/9(-/-)) on the immune response of the CNS to SP infection. To identify the cell populations that mediate the responses to SP, we generated TLR2/4(-/-)-wild-type (wt) bone marrow (BM) chimeras.Results. Compared with infected wt mice, infected TLR2/4(-/-) and TLR2/4/9(-/-) mice had similar reductions in brain cytokine levels, pleocytosis, and cerebral pathologic findings, whereas no such effect was noted in infected TLR4(-/-) mice. The attenuated immune response was paralleled by an impaired host defense that resulted in worsening of disease. Analysis of the chimeric mice after infection showed that mere TLR2/4 deficiency, either of radioresistant cells or of transplanted BM-derived cells, was sufficient to mount a substantial cerebral immune response, such as that noted in wt mice.Conclusion. In murine SP meningitis, TLR2 and TLR4 expressed on radioresistant and transplanted BM-derived cells were major cellular sensors of invading SP inducing inflammatory responses.