Wang Fuan, Gao Xiujuan, Barrett John W, Shao Qing, Bartee Eric, Mohamed Mohamed R, Rahman Masmudur, Werden Steve, Irvine Timothy, Cao Jingxin, Dekaban Gregory A, McFadden Grant
BioTherapeutics Research Group, Robarts Research Institute, London, Ontario, Canada.
PLoS Pathog. 2008 Jul 11;4(7):e1000099. doi: 10.1371/journal.ppat.1000099.
The sensing of pathogen infection and subsequent triggering of innate immunity are key to controlling zoonotic infections. Myxoma virus (MV) is a cytoplasmic DNA poxvirus that in nature infects only rabbits. Our previous studies have shown that MV infection of primary mouse cells is restricted by virus-induced type I interferon (IFN). However, little is known about the innate sensor(s) involved in activating signaling pathways leading to cellular defense responses in primary human immune cells. Here, we show that the complete restriction of MV infection in the primary human fibroblasts requires both tumor necrosis factor (TNF) and type I IFN. We also demonstrate that MV infection of primary human macrophages (pHMs) activates the cytoplasmic RNA sensor called retinoic acid inducible gene I (RIG-I), which coordinately induces the production of both TNF and type I IFN. Of note, RIG-I sensing of MV infection in pHMs initiates a sustained TNF induction through the sequential involvement of the downstream IFN-regulatory factors 3 and 7 (IRF3 and IRF7). Thus, RIG-I-mediated co-induction of TNF and type I IFN by virus-infected pHMs represents a novel innate defense mechanism to restrict viral infection in human cells. These results also reveal a new regulatory mechanism for TNF induction following viral infection.
感知病原体感染并随后触发先天免疫是控制人畜共患病感染的关键。黏液瘤病毒（MV）是一种细胞质DNA痘病毒，在自然界中仅感染兔子。我们之前的研究表明，原代小鼠细胞的MV感染受到病毒诱导的I型干扰素（IFN）的限制。然而，对于参与激活导致原代人类免疫细胞产生细胞防御反应的信号通路的先天传感器知之甚少。在这里，我们表明原代人成纤维细胞中MV感染的完全限制需要肿瘤坏死因子（TNF）和I型干扰素。我们还证明，原代人巨噬细胞（pHM）的MV感染激活了一种名为视黄酸诱导基因I（RIG-I）的细胞质RNA传感器，它协同诱导TNF和I型干扰素的产生。值得注意的是，pHM中RIG-I对MV感染的感知通过下游干扰素调节因子3和7（IRF3和IRF7）的顺序参与启动了持续的TNF诱导。因此，病毒感染的pHM中RIG-I介导的TNF和I型干扰素的共同诱导代表了一种限制人类细胞中病毒感染的新型先天防御机制。这些结果还揭示了病毒感染后TNF诱导的一种新的调节机制。
