A Systems Approach Reveals MAVS Signaling in Myeloid Cells as Critical for Resistance to Ebola Virus in Murine Models of Infection.
A Systems Approach Reveals MAVS Signaling in Myeloid Cells as Critical for Resistance to Ebola Virus in Murine Models of Infection.
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DOI：
10.1016/j.celrep.2016.12.069
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发表时间：
2017-01-17
期刊：
影响因子：
8.8
通讯作者：
Best SM
中科院分区：
文献类型：
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作者：
Dutta M;Robertson SJ;Okumura A;Scott DP;Chang J;Weiss JM;Sturdevant GL;Feldmann F;Haddock E;Chiramel AI;Ponia SS;Dougherty JD;Katze MG;Rasmussen AL;Best SM
2013-16 年史无前例的埃博拉病毒 (EBOV) 爆发导致 11,300 多人死亡。宿主对 RNA 病毒的抵抗需要通过接头蛋白、线粒体抗病毒信号传导 (MAVS) 进行 RIG-I 样受体 (RLR) 信号传导，但 RLR-MAVS 在协调体内抗 EBOV 反应中的作用尚不清楚。在这里，我们对感染野生型或小鼠适应型埃博拉病毒的 MAVS−/− 小鼠应用系统方法。 MAVS 通过表达 IFNα、调节脾脏炎症反应和预防肝脏细胞死亡来控制 EBOV 复制，其中巨噬细胞是影响宿主抵抗力的主要细胞类型。在 LysM+ 骨髓细胞中条件性 MAVS 缺失后，证实了 RLR 信号在巨噬细胞中的主导作用。这些发现揭示了与 EBOV 抗性相关的组织特异性 MAVS 依赖性转录途径，并证明 EBOV 适应引起小鼠疾病涉及两个不同事件的变化，即 RLR-MAVS 拮抗和 RLR 独立的 IFN-I 反应的抑制。
The unprecedented 2013–16 outbreak of Ebola virus (EBOV) resulted in over 11,300 human deaths. Host resistance to RNA viruses requires RIG-I-like receptor (RLR) signaling through the adaptor protein, mitochondrial antiviral signaling (MAVS), but the role of RLR-MAVS in orchestrating anti-EBOV responses in vivo is not known. Here, we apply a systems approach to MAVS−/− mice infected with either wild-type or mouse-adapted EBOV. MAVS controlled EBOV replication through expression of IFNα, regulation of inflammatory responses in the spleen, and prevention of cell death in the liver, with macrophages implicated as a major cell-type influencing host resistance. A dominant role for RLR signaling in macrophages was confirmed following conditional MAVS deletion in LysM+ myeloid cells. These findings reveal tissue-specific MAVS-dependent transcriptional pathways associated with resistance to EBOV, and demonstrate that EBOV adaptation to cause disease in mice involves changes in two distinct events, RLR-MAVS antagonism and suppression of RLR-independent IFN-I responses.