Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Cell Host Microbe. 2020 Nov 11;28(5):712-723.e9. doi: 10.1016/j.chom.2020.09.014. Epub 2020 Oct 27.
Among mammals, bats are particularly rich in zoonotic viruses, including flaviviruses. Certain bat species can be productively yet asymptomatically infected with viruses that cause overt disease in other species. However, little is known about the antiviral effector repertoire in bats relative to other mammals. Here, we report the black flying fox receptor transporter protein 4 (RTP4) as a potent interferon (IFN)-inducible inhibitor of human pathogens in the Flaviviridae family, including Zika, West Nile, and hepatitis C viruses. Mechanistically, RTP4 associates with the flavivirus replicase, binds viral RNA, and suppresses viral genome amplification. Comparative approaches revealed that RTP4 undergoes positive selection, that a flavivirus can mutate to escape RTP4-imposed restriction, and that diverse mammalian RTP4 orthologs exhibit striking patterns of specificity against distinct Flaviviridae members. Our findings reveal an antiviral mechanism that has likely adapted over 100 million years of mammalian evolution to accommodate unique host-virus genetic conflicts.
在哺乳动物中，蝙蝠特别富含人畜共患病毒，包括黄病毒。某些蝙蝠物种可能会无症状地被导致其他物种发病的病毒有效感染。然而，相对于其他哺乳动物，人们对蝙蝠的抗病毒效应子谱知之甚少。在这里，我们报告黑飞狐受体转运蛋白 4（RTP4）是一种有效的干扰素（IFN）诱导物，可抑制黄病毒科家族中的人类病原体，包括寨卡、西尼罗河和丙型肝炎病毒。从机制上讲，RTP4 与黄病毒复制酶结合，结合病毒 RNA，并抑制病毒基因组扩增。比较方法表明，RTP4 经历了正选择，一种黄病毒可以突变以逃避 RTP4 施加的限制，并且不同的哺乳动物 RTP4 直系同源物对不同的黄病毒科成员表现出惊人的特异性模式。我们的研究结果揭示了一种抗病毒机制，该机制可能在 1 亿多年的哺乳动物进化中适应了独特的宿主-病毒遗传冲突。
