Laboratory of Mucosal Immunology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
J Immunol. 2011 Feb 1;186(3):1618-26. doi: 10.4049/jimmunol.1002862. Epub 2010 Dec 27.
Rotavirus is a dsRNA virus that infects epithelial cells that line the surface of the small intestine. It causes severe diarrheal illness in children and ∼500,000 deaths per year worldwide. We studied the mechanisms by which intestinal epithelial cells (IECs) sense rotavirus infection and signal IFN-β production, and investigated the importance of IFN-β production by IECs for controlling rotavirus production by intestinal epithelium and virus excretion in the feces. In contrast with most RNA viruses, which interact with either retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated gene 5 (MDA5) inside cells, rotavirus was sensed by both RIG-I and MDA5, alone and in combination. Rotavirus did not signal IFN-β through either of the dsRNA sensors TLR3 or dsRNA-activated protein kinase (PKR). Silencing RIG-I or MDA5, or their common adaptor protein mitochondrial antiviral signaling protein (MAVS), significantly decreased IFN-β production and increased rotavirus titers in infected IECs. Overexpression of laboratory of genetics and physiology 2, a RIG-I-like receptor that interacts with viral RNA but lacks the caspase activation and recruitment domains required for signaling through MAVS, significantly decreased IFN-β production and increased rotavirus titers in infected IECs. Rotavirus-infected mice lacking MAVS, but not those lacking TLR3, TRIF, or PKR, produced significantly less IFN-β and increased amounts of virus in the intestinal epithelium, and shed increased quantities of virus in the feces. We conclude that RIG-I or MDA5 signaling through MAVS is required for the activation of IFN-β production by rotavirus-infected IECs and has a functionally important role in determining the magnitude of rotavirus replication in the intestinal epithelium.
轮状病毒是一种感染小肠表面上皮细胞的双链 RNA 病毒。它会导致儿童严重腹泻病，全球每年约有 50 万人因此死亡。我们研究了肠道上皮细胞 (IEC) 感知轮状病毒感染并发出 IFN-β 产生信号的机制，调查了 IEC 产生 IFN-β对于控制肠道上皮细胞中轮状病毒的产生和粪便中病毒排泄的重要性。与大多数在细胞内与视黄酸诱导基因 I (RIG-I) 或黑色素瘤分化相关基因 5 (MDA5) 相互作用的 RNA 病毒不同，轮状病毒可单独或联合通过 RIG-I 和 MDA5 被感知。轮状病毒并不通过双链 RNA 传感器 TLR3 或双链 RNA 激活蛋白激酶 (PKR) 发出 IFN-β 信号。沉默 RIG-I 或 MDA5 或它们的共同衔接蛋白线粒体抗病毒信号蛋白 (MAVS) 可显著降低感染 IEC 中的 IFN-β 产生并增加轮状病毒滴度。实验室遗传学和生理学 2 的过表达，这是一种与病毒 RNA 相互作用但缺乏通过 MAVS 进行信号所需的半胱天冬酶激活和募集结构域的 RIG-I 样受体，可显著降低感染 IEC 中的 IFN-β 产生并增加轮状病毒滴度。缺乏 MAVS 的轮状病毒感染小鼠，而不是缺乏 TLR3、TRIF 或 PKR 的小鼠，在肠道上皮细胞中产生的 IFN-β 明显减少，病毒含量增加，粪便中排出的病毒量也增加。我们得出结论，RIG-I 或 MDA5 通过 MAVS 发出的信号对于激活轮状病毒感染的 IEC 中 IFN-β 的产生是必需的，并且在确定肠道上皮细胞中轮状病毒复制的程度方面具有重要的功能作用。
