Department of Pediatrics, University of British Columbia and the Child & Family Research Institute, Vancouver, Canada.
Innate Immun. 2012 Dec;18(6):856-65. doi: 10.1177/1753425912444479. Epub 2012 Apr 25.
TLRs play a key role in innate immune defenses. It was previously reported that purified respiratory syncytial virus (RSV) fusion protein elicits an inflammatory response in hematopoietic cells, which required expression of TLR4 and its co-receptor CD14. However, a biological role of TLR4 in immunity to RSV, as initially proposed, has remained inconclusive and controversial. Here, we directly assess the role of human TLR4 and its co-receptors in NF-κB activation, viral entry and replication using intact virions rather than purified RSV components. We used HEK 293 reporter cells that are highly permissive for RSV and that either express or a lack a functional human TLR4/MD-2/CD14 complex. We demonstrate that RSV-mediated NF-κB activation, viral entry and replication are independent of the expression of a functional human TLR4/MD-2/CD14 complex and that, in turn, human TLR4 activation by LPS remains unaffected in RSV-infected cells. Thus, although isolated viral compounds such as purified RSV F protein may bind TLR4 and/or CD14, a direct interaction between intact RSV particles and the human TLR4 receptor complex does not seem to play a biological role in RSV pathogenesis.
TLRs 在先天免疫防御中发挥关键作用。先前有报道称，纯化的呼吸道合胞病毒（RSV）融合蛋白在造血细胞中引发炎症反应，这需要 TLR4 及其共受体 CD14 的表达。然而，最初提出的 TLR4 在 RSV 免疫中的生物学作用仍然没有定论，存在争议。在这里，我们使用完整的病毒颗粒而不是纯化的 RSV 成分，直接评估人类 TLR4 及其共受体在 NF-κB 激活、病毒进入和复制中的作用。我们使用对 RSV 高度允许的 HEK 293 报告细胞，这些细胞表达或缺乏功能性人类 TLR4/MD-2/CD14 复合物。我们证明 RSV 介导的 NF-κB 激活、病毒进入和复制与功能性人类 TLR4/MD-2/CD14 复合物的表达无关，并且 LPS 激活的人类 TLR4 反过来在 RSV 感染的细胞中不受影响。因此，尽管诸如纯化的 RSV F 蛋白等分离的病毒化合物可能与 TLR4 和/或 CD14 结合，但完整 RSV 颗粒与人类 TLR4 受体复合物之间的直接相互作用似乎在 RSV 发病机制中没有生物学作用。
