A systems biology approach reveals that tissue tropism to West Nile virus is regulated by antiviral genes and innate immune cellular processes.
A systems biology approach reveals that tissue tropism to West Nile virus is regulated by antiviral genes and innate immune cellular processes.
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DOI：
10.1371/journal.ppat.1003168
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发表时间：
2013-02
期刊：
影响因子：
6.7
通讯作者：
Gale M Jr
中科院分区：
文献类型：
--
作者：
Suthar MS;Brassil MM;Blahnik G;McMillan A;Ramos HJ;Proll SC;Belisle SE;Katze MG;Gale M Jr
RIG-I样受体（RLR）和I型干扰素（IFN）信号传导途径的作用对于针对新出现的黄病毒西尼罗河病毒（WNV）的保护性先天免疫应答是必不可少的。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素限制了WNV在外周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明确。使用系统生物学方法，我们定义了限制西尼罗河病毒组织嗜性的宿主先天免疫应答特征和作用。比较WNV感染的允许（脾）和非允许（肝）组织的转录谱分析和途径建模显示出炎症反应的高度富集，包括模式识别受体和IFN信号传导途径，其定义了WNV在肝脏中复制的限制。对来自Mavs−/−×Ifnar−/−小鼠的感染肝脏的评估显示，自然杀伤（NK）细胞信号通路中的几个关键组分的表达丧失，包括与NK细胞活化，炎症细胞因子产生和NK细胞受体信号相关的基因。来自WT小鼠的肝脏免疫细胞浸润的体内分析表明，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−/−感染小鼠的肝脏显示免疫细胞浸润减少，包括NK细胞数量显着减少。树突状细胞和NK细胞的共培养物的分析揭示了RLR和IFN信号通路调节NK细胞效应活性的细胞内在和外在作用。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，驱动组织特异性抗病毒效应基因表达和先天免疫细胞过程，控制组织对西尼罗河病毒感染的向性。西尼罗河病毒（WNV）是一种蚊子传播的RNA黄病毒，是NIAID B类传染性病原体，已在西半球成为严重的公共卫生威胁。限制西尼罗河病毒感染的先天性免疫效应子还没有很好的定义。WNV感染被宿主RIG-I样受体（RLR）感知，RLR是一类模式识别受体，以触发I型干扰素（IFN）和相关的先天免疫防御程序。使用系统生物学方法，我们评估了RLR和I型IFN信号通路在控制组织嗜性方面的贡献。WNV感染触发组织特异性先天免疫应答，特别是抗病毒效应基因和自然杀伤（NK）细胞信号传导相关基因，其直接由RLR和I型IFN信号传导途径的组合作用调节。树突状细胞和NK细胞的共培养显示，RLR和I型IFN信号通路在促进NK细胞活化在WNV感染过程中是必不可少的。我们的观察结果表明，结合RLR和I型IFN依赖性信号程序驱动特定的抗病毒效应基因表达和程序NK细胞反应，一起，用于限制西尼罗河病毒组织嗜性。
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. West Nile virus (WNV), a mosquito-transmitted RNA flavivirus, is an NIAID Category B infectious agent that has emerged in the Western hemisphere as a serious public health threat. The innate immune effectors that impart restriction of WNV infection are not well defined. WNV infection is sensed by the host RIG-I like receptors (RLR), a class of pattern recognition receptors, to trigger type I interferon (IFN) and related innate immune defense programs. Using a systems biology approach, we evaluated the contribution of the RLR and type I IFN signaling pathways in controlling tissue tropism. WNV infection triggers tissue-specific innate immune responses, specifically antiviral effector genes and natural killer (NK) cell signaling related genes, which are directly regulated by the combined actions of the RLR and type I IFN signaling pathways. Cocultures of dendritic and NK cells revealed that RLR and type I IFN signaling pathways are essential in promoting NK cell activation during WNV infection. Our observations indicate that combined RLR- and type I IFN-dependent signaling programs drive specific antiviral effector gene expression and programs NK cell responses that, together, serve to restrict WNV tissue tropism.
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