Xu Ren-Huan, Wong Eric B, Rubio Daniel, Roscoe Felicia, Ma Xueying, Nair Savita, Remakus Sanda, Schwendener Reto, John Shinu, Shlomchik Mark, Sigal Luis J
Immune Cell Development and Host Defense Program, The Research Institute at Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.
Institute of Molecular Cancer Research, University Zurich, 8057 Zurich, Switzerland.
Immunity. 2015 Dec 15;43(6):1148-59. doi: 10.1016/j.immuni.2015.11.015.
Toll-like receptor 9 (TLR9), its adaptor MyD88, the downstream transcription factor interferon regulatory factor 7 (IRF7), and type I interferons (IFN-I) are all required for resistance to infection with ectromelia virus (ECTV). However, it is not known how or in which cells these effectors function to promote survival. Here, we showed that after infection with ECTV, the TLR9-MyD88-IRF7 pathway was necessary in CD11c(+) cells for the expression of proinflammatory cytokines and the recruitment of inflammatory monocytes (iMos) to the draining lymph node (dLN). In the dLN, the major producers of IFN-I were infected iMos, which used the DNA sensor-adaptor STING to activate IRF7 and nuclear factor κB (NF-κB) signaling to induce the expression of IFN-α and IFN-β, respectively. Thus, in vivo, two pathways of DNA pathogen sensing act sequentially in two distinct cell types to orchestrate resistance to a viral disease.
Toll样受体9（TLR9）、其接头蛋白髓样分化因子88（MyD88）、下游转录因子干扰素调节因子7（IRF7）以及I型干扰素（IFN-I）都是抵抗埃可病毒（ECTV）感染所必需的。然而，尚不清楚这些效应因子如何发挥作用或在哪些细胞中发挥作用以促进存活。在此，我们表明，ECTV感染后，TLR9-MyD88-IRF7通路在CD11c(+)细胞中对于促炎细胞因子的表达以及炎性单核细胞（iMos）募集至引流淋巴结（dLN）是必需的。在dLN中，IFN-I的主要产生者是被感染的iMos，其利用DNA传感器接头蛋白干扰素基因刺激蛋白（STING）激活IRF7和核因子κB（NF-κB）信号，分别诱导IFN-α和IFN-β的表达。因此，在体内，DNA病原体感应的两条途径在两种不同的细胞类型中依次发挥作用，以协调对病毒性疾病的抵抗。
