Benitez Asiel Arturo, Spanko Laura Adrienne, Bouhaddou Mehdi, Sachs David, tenOever Benjamin Robert
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Cell Rep. 2015 Nov 17;13(7):1456-1466. doi: 10.1016/j.celrep.2015.10.020. Epub 2015 Nov 5.
Although the intrinsic antiviral cell defenses of many kingdoms utilize pathogen-specific small RNAs, the antiviral response of chordates is primarily protein based and not uniquely tailored to the incoming microbe. In an effort to explain this evolutionary bifurcation, we determined whether antiviral RNAi was sufficient to replace the protein-based type I interferon (IFN-I) system of mammals. To this end, we recreated an RNAi-like response in mammals and determined its effectiveness to combat influenza A virus in vivo in the presence and absence of the canonical IFN-I system. Mammalian antiviral RNAi, elicited by either host- or virus-derived small RNAs, effectively attenuated virus and prevented disease independently of the innate immune response. These data find that chordates could have utilized RNAi as their primary antiviral cell defense and suggest that the IFN-I system emerged as a result of natural selection imposed by ancient pathogens.
尽管许多生物界的内在抗病毒细胞防御利用病原体特异性小RNA，但脊索动物的抗病毒反应主要基于蛋白质，并非专门针对入侵微生物定制。为了解释这种进化分歧，我们确定抗病毒RNA干扰是否足以取代哺乳动物基于蛋白质的I型干扰素（IFN-I）系统。为此，我们在哺乳动物中重建了类似RNA干扰的反应，并确定其在存在和不存在经典IFN-I系统的情况下在体内对抗甲型流感病毒的有效性。由宿主或病毒衍生的小RNA引发的哺乳动物抗病毒RNA干扰有效地减轻了病毒感染并独立于先天免疫反应预防了疾病。这些数据表明，脊索动物本可以利用RNA干扰作为其主要的抗病毒细胞防御，并表明IFN-I系统是古代病原体施加的自然选择的结果。
