TLR-mediated inflammatory responses to Streptococcus pneumoniae are highly dependent on surface expression of bacterial lipoproteins.
TLR-mediated inflammatory responses to Streptococcus pneumoniae are highly dependent on surface expression of bacterial lipoproteins.
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DOI：
10.4049/jimmunol.1401413
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发表时间：
2014-10-01
期刊：
影响因子：
--
通讯作者：
Brown J
中科院分区：
文献类型：
--
作者：
Tomlinson G;Chimalapati S;Pollard T;Lapp T;Cohen J;Camberlein E;Stafford S;Periselneris J;Aldridge C;Vollmer W;Picard C;Casanova JL;Noursadeghi M;Brown J
肺炎链球菌感染会诱导炎症反应，从而促进疾病发病机制和免疫，但介导这些影响的宿主-病原体相互作用尚不清楚。我们使用表面脂蛋白缺陷的 Δlgt 肺炎球菌突变株来检验脂蛋白是 TLR 介导的肺炎链球菌免疫反应的关键决定因素的假设。我们使用报告基因检测表明，TLR2 信号传导依赖于肺炎球菌脂蛋白，并且巨噬细胞 NF-κB 激活和 TNF-α 释放因 Δlgt 菌株而减少。 TLR2 缺陷小鼠的巨噬细胞消除了 Δlgt 和野生型细菌之间 TNF-α 反应的差异，但 TLR4 缺陷小鼠的巨噬细胞则没有。人类巨噬细胞的转录谱揭示了对 Δlgt 肺炎链球菌的 TLR2 相关反应减弱，其中包括许多 NF-κB 调节的促炎细胞因子和趋化因子基因。重要的是，非 TLR2 相关反应得以保留。使用来自 IL-1R 相关激酶 4 缺陷患者的白细胞和小鼠肺炎模型进行的实验证实，促炎反应是脂蛋白依赖性的。我们的数据表明，白细胞对细菌脂蛋白的反应是 TLR2 和 IL-1R 相关激酶 4 介导的肺炎链球菌炎症反应所必需的。
Streptococcus pneumoniae infections induce inflammatory responses that contribute toward both disease pathogenesis and immunity, but the host–pathogen interactions that mediate these effects are poorly defined. We used the surface lipoprotein-deficient ∆lgt pneumococcal mutant strain to test the hypothesis that lipoproteins are key determinants of TLR-mediated immune responses to S. pneumoniae. We show using reporter assays that TLR2 signaling is dependent on pneumococcal lipoproteins, and that macrophage NF-κB activation and TNF-α release were reduced in response to the ∆lgt strain. Differences in TNF-α responses between Δlgt and wild-type bacteria were abrogated for macrophages from TLR2- but not TLR4-deficient mice. Transcriptional profiling of human macrophages revealed attenuated TLR2-associated responses to ∆lgt S. pneumoniae, comprising many NF-κB–regulated proinflammatory cytokine and chemokine genes. Importantly, non-TLR2–associated responses were preserved. Experiments using leukocytes from IL-1R–associated kinase-4–deficient patients and a mouse pneumonia model confirmed that proinflammatory responses were lipoprotein dependent. Our data suggest that leukocyte responses to bacterial lipoproteins are required for TLR2- and IL-1R–associated kinase-4–mediated inflammatory responses to S. pneumoniae.
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