Department of Immunology, University of Washington School of Medicine, Seattle, Washington, USA.
PLoS Pathog. 2013 Feb;9(2):e1003168. doi: 10.1371/journal.ppat.1003168. Epub 2013 Feb 7.
The actions of the RIG-I like receptor (RLR) and type I interferon (IFN) signaling pathways are essential for a protective innate immune response against the emerging flavivirus West Nile virus (WNV). In mice lacking RLR or IFN signaling pathways, WNV exhibits enhanced tissue tropism, indicating that specific host factors of innate immune defense restrict WNV infection and dissemination in peripheral tissues. However, the immune mechanisms by which the RLR and IFN pathways coordinate and function to impart restriction of WNV infection are not well defined. Using a systems biology approach, we defined the host innate immune response signature and actions that restrict WNV tissue tropism. Transcriptional profiling and pathway modeling to compare WNV-infected permissive (spleen) and nonpermissive (liver) tissues showed high enrichment for inflammatory responses, including pattern recognition receptors and IFN signaling pathways, that define restriction of WNV replication in the liver. Assessment of infected livers from Mavs(-/-) × Ifnar(-/-) mice revealed the loss of expression of several key components within the natural killer (NK) cell signaling pathway, including genes associated with NK cell activation, inflammatory cytokine production, and NK cell receptor signaling. In vivo analysis of hepatic immune cell infiltrates from WT mice demonstrated that WNV infection leads to an increase in NK cell numbers with enhanced proliferation, maturation, and effector action. In contrast, livers from Mavs(-/-) × Ifnar(-/-) infected mice displayed reduced immune cell infiltration, including a significant reduction in NK cell numbers. Analysis of cocultures of dendritic and NK cells revealed both cell-intrinsic and -extrinsic roles for the RLR and IFN signaling pathways to regulate NK cell effector activity. Taken together, these observations reveal a complex innate immune signaling network, regulated by the RLR and IFN signaling pathways, that drives tissue-specific antiviral effector gene expression and innate immune cellular processes that control tissue tropism to WNV infection.
RLR 样受体（RLR）和 I 型干扰素（IFN）信号通路的作用对于针对新兴的黄病毒西尼罗河病毒（WNV）的保护性先天免疫反应至关重要。在缺乏 RLR 或 IFN 信号通路的小鼠中，WNV 表现出增强的组织嗜性，表明先天免疫防御的特定宿主因子限制了 WNV 在周围组织中的感染和传播。然而，RLR 和 IFN 途径协调和发挥作用以限制 WNV 感染的免疫机制尚未得到很好的定义。使用系统生物学方法，我们定义了宿主先天免疫反应特征和限制 WNV 组织嗜性的作用。比较 WNV 感染的允许（脾脏）和非允许（肝脏）组织的转录谱分析和途径建模显示，炎症反应高度富集，包括模式识别受体和 IFN 信号通路，这些反应定义了 WNV 在肝脏中的复制限制。评估 Mavs(-/-) × Ifnar(-/-) 小鼠感染的肝脏显示，几种关键的 NK 细胞信号通路内的基因表达丢失，包括与 NK 细胞激活、炎症细胞因子产生和 NK 细胞受体信号相关的基因。来自 WT 小鼠的感染肝脏的体内分析表明，WNV 感染导致 NK 细胞数量增加，增殖、成熟和效应作用增强。相比之下，来自 Mavs(-/-) × Ifnar(-/-) 感染的肝脏显示出免疫细胞浸润减少，包括 NK 细胞数量的显著减少。树突状细胞和 NK 细胞共培养分析揭示了 RLR 和 IFN 信号通路调节 NK 细胞效应活性的细胞内和细胞外作用。总之，这些观察结果揭示了一个复杂的先天免疫信号网络，由 RLR 和 IFN 信号通路调节，该网络驱动组织特异性抗病毒效应基因表达和控制组织嗜性的先天免疫细胞过程。
