Differential role for TLR3 in respiratory syncytial virus-induced chemokine expression
Differential role for TLR3 in respiratory syncytial virus-induced chemokine expression
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DOI：
10.1128/jvi.79.6.3350-3357.2005
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发表时间：
2005-03-01
影响因子：
5.4
通讯作者：
Lukacs, NW
中科院分区：
文献类型：
--
作者：
Rudd, BD;Burstein, E;Lukacs, NW
呼吸道合胞病毒（RSV）是全球婴幼儿下呼吸道感染的主要原因。先前的研究报道了白细胞介素-8/CXCL8和RANTES/CCL5的诱导与人类疾病严重程度相关。这些趋化因子的产生是由病毒复制引起的，并且依赖于nf - κ b。RSV是一种负义单链RNA病毒，需要全长正义RNA合成新的病毒RNA。我们的研究目的是探讨RSV的活跃病毒复制是否可以通过tlr3介导的信号通路引起趋化因子的产生。在tlr3转染的HEK 293细胞中，与载体对照相比，活RSV以时间和剂量依赖的方式优先激活趋化因子。RSV还显示上调人肺成纤维细胞和上皮细胞（MRC-5和A549）的TLR3。用小干扰RNA靶向TLR3表达可降低IP-10/CXCL10和CCL5的合成，但未显著降低CXCL8的水平。阻断接合蛋白MyD88的表达确定了MyD88在CXCL8产生中的作用，而发现CCL5的合成与MyD88无关。RSV直接通过TLR3信号通路诱导CCL5的产生，不需要干扰素（IFN）通过IFN- α / β受体信号传导。TLR3不影响病毒复制，因为尽管TLR3表达改变，但从rsv感染的细胞中恢复了相同的病毒载量。综上所述，我们的研究表明TLR3介导rsv感染上皮细胞的炎症细胞因子和趋化因子的产生。
Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in young infants worldwide. Previous studies have reported that the induction of interleukin-8/CXCL8 and RANTES/CCL5 correlates with disease severity in humans. The production of these chemokines is elicited by viral replication and is NF-kappaB dependent. RSV, a negative-sense single-stranded RNA virus, requires full-length positive-sense RNA for synthesis of new viral RNA. The aim of our studies was to investigate whether active viral replication by RSV could evoke chemokine production through TLR3-mediated signaling pathways. In TLR3-transfected HEK 293 cells, live RSV preferentially activated chemokines in both a time- and dose-dependent manner compared to vector controls. RSV was also shown to upregulate TLR3 in human lung fibroblasts and epithelial cells (MRC-5 and A549). Targeting the expression of TLR3 with small interfering RNA decreased synthesis of IP-10/CXCL10 and CCL5 but did not significantly reduce levels of CXCL8. Blocking the expression of the adapter protein MyD88 established a role for MyD88 in CXCL8 production, whereas CCL5 synthesis was found to be MyD88 independent. Production of CCL5 by RSV was induced directly through TLR3 signaling pathways and did not require interferon (IFN) signaling through the IFN-alpha/beta receptor. TLR3 did not affect viral replication, since equivalent viral loads were recovered from RSV-infected cells despite altered TLR3 expression. Taken together, our studies indicate that TLR3 mediates inflammatory cytokine and chemokine production in RSV-infected epithelial cells.